Catechol derivatives

ABSTRACT

Catechol derivatives of the formula ##STR1## wherein Ra, Rb and Rc have the significance given herein, the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adenosylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuronal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure. 
     Formula Ia above embraces not only compounds which form part of the invention, but also known compounds; the compounds which form part of the invention can be prepared according to known methods.

This is a continuation of application Ser. No. 07/686,210, filed Apr.16, 1991, now U.S. Pat. No. 5,236,952, which is a Rule 60 Continuationof Ser. No. 07/395,110, filed Aug. 16, 1989, now Abandoned, which is aRule 60 Continuation of Ser. No. 022,891, filed Mar. 6, 1987, nowAbandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to catechol derivatives of the formula ##STR2##wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is halogen,nitro, cyano or the group -(A)_(n) -(Q)_(m) -R¹ or -(A)_(n) -Q-R². A isvinylene optionally substituted by lower alkyl, n is the integer 0 or 1,m is the integer 0 or 1, R¹ is the group -COR³, an aromatic carbocyclicgroup, or an aromatic or partially unsaturated heterocyclic groupattached via a carbon atom. R² is hydrogen or an optionally substituted,saturated or partially unsaturated lower hydrocarbon residue, R³ ishydroxy, amino, an optionally substituted, saturated or partiallyunsaturated, lower hydrocarbon residue attached via an oxygen atom or animino or lower alkylimino group or a saturated, N-containingheterocyclic group attached via a ring nitrogen atom, Q is the group-CO- or >C=N-(Z)_(p) -R⁴, Z is an oxygen atom or an imino group, p isthe integer 0 or 1 and R⁴ is hydrogen or a saturated or partiallyunsaturated, lower hydrocarbon residue which is optionally substitutedand which is optionally attached via a carbonyl group.

the ester and ether derivatives thereof which are hydrolyzable underphysiological conditions and the pharmaceutically acceptable saltsthereof. The compounds of formula Ia possess valuable pharmacologicalproperties. In particular, these compounds inhibit the enzymecatechol-O-methyltransferase (COMT), a soluble, magnesium-dependentenzyme which catalyzes the transference of the methyl group ofS-adenosylmethionine to a catechol substrate, whereby the correspondingmethyl ethers are formed. Suitable substrates which can be O-methylatedby COMT and which can thus be deactivated are, for example,extraneuronal catecholamines and exogenously-administeredtherapeutically active substances having a catechol structure.

The compounds of formula Ia above can accordingly be used in theprevention or control of illnesses in which a deactivation ofextraneuronal catecholamines by COMT plays a role, for example, in theprevention or control of depressions. In this case the compounds offormula Ia above can be used as individual compounds or in combinationwith other therapeutically active substances which favorably influencethe course of the illness. The compounds of formula Ia can, however,also be used as co-medications with other therapeutically activesubstances.

The compounds of formula Ia can, however, also be used to improve theprevention or control of illnesses with therapeutically activesubstances which have a catechol structure. The treatment of Parkinson'sdisease and of parkinsonism with L-dopa, a therapeutically activesubstance having the catechol structure, can be mentioned as an example.In such cases the compounds of formula Ia can be used in the form of aco-medication or as combination preparations.

The field of diagnostics offers a further possibility for the use of thecompounds of formula Ia above. After the administration of [¹⁸F]-6-fluoro-L-dopa. [¹⁸ F]-dopamine in the brain can be visualized withthe aid of positron emission tomography. By adding a compound of formulaIa above, the COMT is inhibited and thus the formation of [¹⁸F]-3-O-methyldopa is prevented. In the absence of a COMT-inhibitor, the[¹⁸ F]-3-O-methyldopa would penetrate into the brain and lead to agreatly increased background which would make the diagnosis very muchmore difficult.

DETAILED DESCRIPTION OF THE INVENTION

The catechol derivatives of the invention are characterized by theformula ##STR3##

wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is halogen,nitro, cyano or the group -(A)_(n) -(Q)_(m) -R¹ or -(A)_(n) -Q-R². A isvinylene optionally substituted by lower alkyl, n is the integer 0 or 1,m is the integer 0 or 1, R¹ is the group -COR³ an aromatic carbocyclicgroup, or an aromatic or partially unsaturated heterocyclic groupattached via a carbon atom, R² is hydrogen or an optionally substituted,saturated or partially unsaturated lower hydrocarbon residue. R³ ishydroxy, amino, an optionally substituted, saturated or partiallyunsaturated, lower hydrocarbon residue attached via an oxygen atom or animino or lower alkylimino group or a saturated, N-containingheterocyclic group attached via a ring nitrogen atom, Q is the group-CO- or >C=N-(Z)_(p) -R⁴, Z is an oxygen atom or an imino group, p isthe integer 0 or 1 and R⁴ is hydrogen or a saturated or partiallyunsaturated, lower hydrocarbon residue which is optionally substitutedand which is optionally attached via a carbonyl group,

including the ester and ether derivatives thereof which are hydrolyzableunder physiological conditions and the pharmaceutically acceptable saltsthereof. The compounds of formula Ia possess valuable pharmacologicalproperties. In particular, these compounds inhibit the enzymecatechol-O-methyltransferase (COMT), a soluble, magnesium-dependentenzyme which catalyzes the transference of the methyl group ofS-adenosylmethionine to a catechol substrate, whereby the correspondingmethyl ethers are formed. Suitable substrates which can be O-methylatedby COMT and which can thus be deactivated are, for example,extraneuronal catecholamines and exogenously-administeredtherapeutically active substances having a catechol structure.

The compounds of formula Ia above can accordingly be used in theprevention or control of illnesses in which a deactivation ofextraneuronal catecholamines by COMT plays a role, for example, in theprevention or control of depressions. In this case, the compounds offormula Ia above can be used as individual compounds or in combinationwith other therapeutically active substances which favorably influencethe course of the illness. The compounds of formula Ia can, however,also be used as co-medications with other therapeutically activesubstances.

The compounds of formula Ia can, however, also be used to improve theprevention or control of illnesses with therapeutically activesubstances which have a catechol structure. The treatment of Parkinson'sdisease and of parkinsonism with L-dopa, a therapeutically activesubstance having the catechol structure, can be mentioned as an example.In such cases the compounds of formula Ia can be used in the form of aco-medication or as combination preparations.

The field of diagnostics offers a further possibility for the use of thecompounds of formula Ia above. After the administration of [¹⁸F]-6-fluoro-L-dopa. [¹⁸ F]-dopamine can be visualized in the brain withthe aid of positron emission tomography. By adding a compound of formulaIa above, the COMT is inhibited and thus the formation of [¹⁸F]-3-O-methyldopa is prevented. In the absence of a COMT-inhibitor, the[¹⁸ F]-3-O-methyldopa would penetrate into the brain and lead to agreatly increased background which would make the diagnosis very muchmore difficult.

Formula Ia above embraces not only known, but also compounds which formpart of the invention. The compounds of formula Ia which are known fallunder the formula ##STR4##

wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc" is nitro,cyano or the group -(A)_(n) -COOH or -(A)_(n) -Q-H. A is vinyleneoptionally substituted by lower alkyl, n is the number 0 or 1, Q is thegroup -CO- or >C-N-(Z)_(p) -R⁴, Z is an oxygen atom or an imino group, pis the number 0 or 1 and R⁴ is hydrogen or a saturated or partiallyunsaturated lower hydrocarbon residue which is optionally substitutedand which is optionally attached via a carbonyl group, with the provisothat Ra is nitro when Rc" is cyano or nitro,

and ester and ether derivatives thereof which are hydrolyzable underphysiological conditions and the pharmaceutically acceptable saltsthereof.

The compounds of formula Ia which form part of the invention are thecompounds of the formula ##STR5##

wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc' is nitro,cyano or the group -(A)_(n) -(Q)_(m) -R¹¹ or -(A)_(n) -Q-R²¹. A isvinylene optionally substituted by lower alkyl, n is the number 0 or 1,m is the number 0 or 1, R¹¹ is the group -COR³¹, an aromatic carbocyclicgroup, or an aromatic or partially unsaturated heterocyclic groupattached via a carbon atom. R²¹ is an optionally substituted, saturatedor partially unsaturated lower hydrocarbon residue, R³¹ is hydroxy,amino, an optionally substituted, saturated or partially unsaturatedlower hydrocarbon residue attached via an oxygen atom or an imino orlower alkylimino group or a saturated, N-containing heterocyclic groupattached via a ring nitrogen atom, Q is the group -CO- or >C=N-(Z)_(p)-R⁴, Z is an oxygen atom or an imino group, p is the number 0 or 1 andR⁴ is hydrogen or a saturated or partially unsaturated, lowerhydrocarbon residue which is optionally substituted and which isoptionally attached via a carbonyl group, with the proviso that Ra iscyano when Rc' is cyano or nitro and R³¹ has a significance differentfrom hydroxy when m is the number 0,

and the ester and ether derivatives thereof which are hydrolyzable underphysiological conditions and the pharmaceutically acceptable saltsthereof.

Objects of the invention are: The above compounds of formula Ia and thementioned derivatives thereof for use as therapeutically activesubstances: medicaments based on these compounds and derivatives: thepreparation of such medicaments; the use of the compounds andderivatives in question in the prevention or control of illnesses; theuse of the compounds and derivatives in question for the preparation ofmedicaments which in a given case inhibit the enzyme COMT in the senseof a desired side-effect; the compounds of formula Ib above and thementioned derivatives thereof; the preparation of these compounds andderivatives; as well as intermediates for their preparation.

The term "lower" denotes residues and compounds with a maximum of 7,preferably a maximum of 4, carbon atoms. The term "alkyl", taken aloneor in combinations, such as, "alkyl group", "alkoxy", "alkylthio" and"alkylimino", denotes straight-chain or branched, saturated hydrocarbonresidues, for example, such as methyl, ethyl, propyl, isopropyl,n-butyl, s-butyl, i-butyl, t-butyl and the like. The term "saturated orpartially unsaturated lower hydrocarbon residue" denotes open-chain andcyclic groups and combinations thereof. Examples of saturated andpartially unsaturated lower hydrocarbon residues are: lower alkyl groupssuch as those defined above: lower alkenyl groups, for example,2-propenyl, 2-butenyl, 3-butenyl and 2-methyl-2-propenyl; C₃₋₇-cycloalkyl and C₈₋₁₀ -bicycloalkyl groups optionally substituted bylower alkyl groups, for example, cyclopropyl, cyclopentyl,2-methylcyclopentyl, cyclohexyl and 3-methylcyclohexyl; lowercycloalkenyl groups optionally substituted by lower alkyl groups, forexample, 3-cyclopentenyl, 1-methyl-3-cyclopentenyl and 3-cyclohexenyl;lower alkyl or alkenyl groups substituted by lower cycloalkyl orcycloalkenyl groups, for example, cyclopropylmethyl, cyclopropylethyl,cyclopentylmethyl, cyclohexylmethyl, 2 -cyclohexenylmethyl and3-cyclopropyl-2-propenyl. The lower alkenyl groups preferably contain2-4 carbon atoms; the cycloalkyl and cycloalkenyl groups preferablycontain 3-6 carbon atoms.

The following come into consideration as substituents for the abovelower hydrocarbon residues: Hydroxy, cyano, nitro, halogen, amino, loweralkylamino, di(lower alkyl)-amino, lower alkoxy, lower alkoxycarbonyl,aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, loweralkanoyloxy, lower alkanoyl, carbamoyl, mono- or di(loweralkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, loweralkanoylamino, lower alkoxycarbonylamino and lower alkylthio. Thesaturated or partially unsaturated lower hydrocarbon residues arepreferably unsubstituted or mono- or disubstituted.

The term "aryl" denotes carbocyclic aromatic groups, preferably mono- orbicyclic groups. Especially preferred carbocyclic aromatic groups arephenyl and naphthyl, especially phenyl. These groups are optionallysubstitued by: halogen, trifluoromethyl, nitro, amino, mono- or di(loweralkyl)amino, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl,lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy,carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, loweralkanoylamino or lower alkoxycarbonylamino. The carbocyclic aromaticgroups are preferably unsubstituted or mono- or disubstituted.

The term "aromatic or partially unsaturated heretocyclic group"preferably denotes a mono-, di- or tricyclic, aromatic or partiallyunsaturated, heterocyclic group with up to 5 hereto atoms from the groupconsisting of nitrogen, sulfur and oxygen. The heterocyclic groupspreferably contain 1-4 nitrogen atoms and/or an oxygen or sulfur atom.They are preferably mono- or bicyclic. The hereto atoms are preferablydistributed on one or two rings, whereby nitrogen atoms cansimultaneously also be components of 2 rings. The heterocyclic groupsare preferably aromatic. They can be substituted and are preferablymono- , di- or trisubstituted. As substituents there come intoconsideration: halogen, trifluoromethyl, nitro, carboxy, amino,arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl,lower alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto,lower alkylthio, lower alkylamino, di(lower alkyl)amino, C₃₋₇-cycloalkylamino, C₈₀₋₁₀ -bicycloalkylamino, lower alkanoylamino, loweralkoxycarbonylamino, carbamoyl, mono- or di(lower alkyl)carbamoyl,cyano, aryl, aryl-lower alkyl, aryl-lower alkylamino, heteroaryl,heteroaryl-lower alkyl, heteroarylamino and C3-7-cycloalkyl. Themonocyclic heterocyclic groups are preferably 5- or 6-membered andcontain a maximum of four hereto atoms. The bicyclic heterocyclic groupsare preferably 8- to 10-membered, with the individual rings beingpreferably 5- or 6-membered.

The following are to be mentioned as examples of such heterocyclicgroups: Pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl,oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl,quinolinyl, isoquinolinyl, dihydroisoquinolinyl, benzoxazinyl,quinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl,imidazothiadiazolyl, imidazopyridyl, benzothiazinyl, benzoquinoxalinyland imidazobenzothiazolyl.

The term "heteroaryl" denotes aromatic heterocyclic groups, as definedabove.

The term "a saturated, N-containing heterocyclic group attached via aring nitrogen atom" preferably denotes a 3- to 7-membered, preferably 4-to 6-membered, saturated N-heterocycle which, in addition to the saidnitrogen atom, can contain an oxygen, sulfur or nitrogen atom as asecond hereto atom. These saturated N-heterocycles can be mono- ordisubstituted by: lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy,lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, loweralkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di(loweralkyl)-carbamoyl, oxo and/or lower alkylenedioxy.

The following are to be mentioned as examples of such N-containingheterocyclic groups: 4-morpholinyl, 1-pyrrolidinyl and 1-azetidinyl.

The ester and ether derivatives which are hydrolyzable underphysiological conditions are preferably compounds of formula Ia in whichat least one of the two phenolic hydroxy groups is acylated by a lowerfatty acid or etherified by a lower 1-alkoxycarbonyloxy-1-alkyl, lower1-alkanoyloxy-1-alkyl or by a lower 2-oxo-1-alkyl group.

The substituent Ra preferably is nitro. The substituent Rb is preferablysituated in the p-position to the substituent Ra and preferably ishydrogen, chlorine or fluorine, with hydrogen being especiallypreferred. The substituent Rc' preferably is the group -CO-R¹¹ in whichR¹¹ is an aromatic, mononuclear carbocyclic group or an aromatic,mononuclear heterocyclic group with 1-3 nitrogen atoms as the heteroring member(s) which is attached via a carbon atom. In an especiallypreferred embodiment R¹¹ is a phenyl group optionally mono- ordisubstituted by halogen, trifluoromethyl, cyano, hydroxy or loweralkyl, or a pyridyl group.

Particularly preferred compounds of the invention are:

3,4-Dihydroxy-5-nitrobenzophenone,

2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone and

3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketone.

The compounds of formula Ib, the ester and ether derivatives thereofwhich are hydrolyzable under physiological conditions and thepharmaceutically acceptable salts thereof can be prepared in accordancewith the invention by

a) cleaving the lower alkyl ether group(s) in a compound of the formula##STR6##

wherein one of the symbols R and R' is lower alkyl and the other ishydrogen or lower alkyl and Ra, Rb and Rc' have the above significance,or

b) reacting a compound of the formula ##STR7##

wherein X is a leaving group and Ra, Rb, A and n have the abovesignificance.

with a thioamide, thiourea, thiocarboxylic acid hydrazide,thiosemicarbazide, amidine, guanidine, amidrazone, aminoguanidine,cyclic amidine, 1,2-diamine, 1,2-aminothiol or a 1,2-aminoalcohol and,if desired, dehydrogenating the cyclocondensation product obtained, or

c) reacting a compound of the formula ##STR8##

wherein R" is lower alkyl and Ra, Rb, A and n have the abovesignificance.

with a 1,2-diamine, 1,2-aminothiol, 1,2-aminoalcohol, semicarbazide,thiosemicarbazide, amidrazone or an aminoguanidine and, if desired,dehydrogenating the cyclocondensation product obtained, or

d) reacting a compound of formula Ib¹ above with a β-aminocarbonylcompound, or

e) converting the carboxaldehyde group(s) in a compound of the formula##STR9##

wherein Rc"' is nitro, cyano or the group -(A)_(n) -R¹² and R¹² is thegroup -COR³¹, an aromatic carbocyclic group, or an aromatic or partiallyunsaturated heterocyclic group attached via a carbon atom and Ra, Rb, A,n and R³¹ have the above significance,

or in a di-O-lower alkanoyl derivative thereof into the cyano group(s),or

f) reacting a di-O-lower alkanoyl derivative of a carboxylic acid of theformula ##STR10##

wherein Ra, Rb, A and n have the above significance, in the presence ofa condensation agent or a reactive derivative or a di-O-lower alkanoylderivative of a carboxylic acid of formula Ia³ or Ib³ with a compound ofthe formula

    HO-R.sup.5 V or HNR.sup.6 R.sup.7                          VI

wherein R⁵ is an optionally substituted, saturated or partiallyunsaturated, lower hydrocarbon residue, R⁶ is hydrogen or lower alkyland R⁷ is hydrogen or an optionally substituted, saturated or partiallyunsaturated lower hydrocarbon residue or R⁶ and R⁷ taken together withthe nitrogen atom signify a saturated N-containing heterocyclic group,or

g) hydrolyzing a compound of formula Ib² or a compound of the formula##STR11##

wherein R⁸ is lower alkanoyl and Ra, Rb and Rc' have the abovesignificance, or

h) reacting a compound of the formula ##STR12##

wherein Ra and Rb have the above significance and R"' is hydrogen orlower alkyl,

or a di-O-lower alkanoyl derivative thereof in the presence of asecondary amine with a compound of the formula

    CH.sub.3 CO-R.sup.23                                       VII

wherein R²³ is an optionally substituted, saturated or partiallyunsaturated lower hydrocarbon residue, or

i) reacting a compound of the formula ##STR13##

wherein Ra, Rb, A, n and R" have the above significance, with ahydrazine or an amidine, or

j) reacting a compound of formula Ib above in which m is the integer 1and Q is the group -CO- with a compound of the formula

    H.sub.2 N-(Z).sub.p -R.sup.4                               VIII

wherein Z, p and R⁴ have the above significance, and, if desired,

k) converting a compound of formula Ib above into an ester or etherderivative which is hydrolyzable under physiological conditions or intoa pharmaceutically acceptable salt thereof.

In accordance with process variant a) the compounds of formula Ib can beprepared by cleaving the ether group(s) in a compound of formula II.This ether cleavage can be carried out according to known methods whichare familiar to any person skilled in the art. The ether cleavage can becarried out, for example, by treatment with hydrogen bromide in asuitable solvent. Suitable solvents are, for example, water, acetic acidand mixtures thereof. The reaction is preferably carried out at anelevated temperature, for example in a temperature range of about 100°C. to the boiling temperature of the reaction mixture. There arepreferably used 48 percent hydrobromic acid or mixtures thereof withacetic acid.

The ether cleavage can also be carried out by treatment with borontribromide in a suitable solvent at temperatures of about -60° C. toabout room temperature.

Suitable solvents are especially halogenated lower hydrocarbons, suchas, methylene chloride, chloroform and the like. Other suitable methodsare: treatment with pyridinium hydrochloride at temperatures of about150° C. to about 250° C. and treatment with sodium iodide/silicontetrachloride in an inert organic solvent at an elevated temperature,for example, at the reflux temperature of the reaction mixture. Suitablesolvents for the latter process are, for example, acetonitrile, aromatichydrocarbons, such as, benzene or toluene, mixtures thereof and thelike.

In accordance with process variant b) there can be prepared compounds ofthe formula ##STR14##

wherein Ra, Rb, A and n have the above significance and Q¹ is a group ofthe formula ##STR15##

in which Re is hydrogen, C₃₋₇ -alkyl, C₃₋₇ -cycloalkyl, aryl,heteroaryl, aryl-lower alkyl or heteroaryl-lower alkyl, Rf is hydrogen,aryl, aryl-lower alkyl, lower alkyl, lower alkoxycarbonyl, heteroaryl,heteroaryl-lower alkyl, C₈₋₁₀ -bicycloalkyl or C₃₋₇ -cycloalkyl, Rg andRh each are independently hydrogen, cyano, lower alkyl, C₃₋₇-cycloalkyl, aryl, aryl-lower alkyl, heteroaryl or heteroaryl-loweralkyl or Rg and Rh taken together with the two carbon atoms to whichthey are attached are an aromatic carboxycyclic group, or an aromatic orpartially unsaturated heterocyclic group, the dotted line is an optionalbond and Q⁴ taken together with the carbon atom and the nitrogen atomsignify an aromatic or partially unsaturated, heterocyclic group whichcontains at least one nitrogen atom as a hereto ring member.

Suitable solvents for this process aspect are lower alcohols such asethanol, n-butanol, n-hexanol and ethylene glycol, open-chain and cyclicethers which can contain free hydroxy groups, for example,tetrahydrofuran, dioxane, t-butyl methyl ether, ethylene glycol dimethylether, diethylene glycol dimethyl ether, ethylene glycol monomethylether and diethylene glycol monomethyl ether, acetonitrile,dimethylformamide, dimethylacetamide and dimethyl sulfoxide. The desiredreaction can also be carried out without a solvent by dry heating thereaction partners. The reaction is preferably carried out at an elevatedtemperature, for example, in a range of about 50° C. to 150° C., wherebyit is preferably carried out at the boiling temperature of the solventinsofar as it is carried out in the presence of a solvent and theboiling point lies in the previously mentioned range.

In accordance with process variant c) there can be prepared compounds ofthe formula ##STR16##

in which Ra, Rb, A and n have the above significance and Q² is a groupof the formula ##STR17##

in which Re, Rf, Rg, Rh and the dotted line have the above significance.

The reaction in accordance with process variant c) can be carried outunder the same reaction conditions as process variant b).

In accordance with process variant d) there can be prepared compounds ofthe formula ##STR18##

wherein Q³ is the group of the formula ##STR19##

and Ra, Rb, Re, Rf, Rg, Rh, A, n and the dotted line have the abovesignificance.

Process variant d) can also be carried out under the same reactionconditions as process variant b).

In accordance with process variant e) there can be prepared compounds offormula Ib in which Ra is cyano, Rc' is nitro, cyano or the group-(A)_(n) -R¹² and R¹² is the group -COR³¹, an aromatic carbocyclic groupor an aromatic or partially unsaturated heterocyclic group attached viaa carbon atom and Rb, A, n and R³¹ have the above significance. Theconversion of the carboxaldehyde group(s) into the cyano group(s) can beeffected according to known methods which are familiar to any personskilled in the art. For example, a compound of formula Ia², III or IVcan be treated with hydroxylamine O-sulfonic acid at an elevatedtemperature, with water being preferably used as the solvent. Thereaction can be carried out in a temperature range of about 50° C. toabout 100° C.

In accordance with process variant f) there can be prepared di-O-loweralkanoyl derivatives of compounds of formula Ib in which Rc' is thegroup -(A)_(n) -(CO)_(m) -COR³² and R³² is amino, an optionallysubstituted, saturated or partially unsaturated, lower hydrocarbonresidue attached via an oxygen atom or an imino or lower alkyliminogroup or a saturated, N-containing heterocyclic group attached via aring nitrogen atom and A, n and m have the above significance. Thisreaction can also be carried out according to known methods which arefamiliar to any person skilled in the art. Lower alkyl esters can beprepared, for example, by treating the carboxylic acid with thecorresponding lower alcohol in the presence of an acid, with thecorresponding lower alcohol being preferably used as the solvent.Suitable acids are, for example, mineral acids such as hydrogen chlorideand organic sulfonic acids such as p-toluenesulfonic acid. The reactiontemperature preferably lies in a range of room temperature to theboiling temperature of the chosen solvent.

The remaining esters and the amides are preferably prepared startingfrom reactive carboxylic acid derivatives. Suitable reactive carboxylicacid derivatives are, for example, the corresponding carboxylic acidhalides, especially the carboxylic acid chlorides, correspondingcarboxylic acid anhydrides and mixed anhydrides, for example, withtrifluoroacetic acid and organic sulfonic acids such asmesitylenesulfonic acid and p-toluenesulfonic acid, correspondingcarboxylic acid imidazolides and the like. The reaction is convenientlycarried out in the presence of an acid-binding agent and in an inertorganic solvent. Suitable acid-binding agents are, for example, tertiaryamines such as triethylamine and pyridine. In the preparation of amides,excess amine of formula VI can also be used as the acid-binding agent.Suitable solvents are, for example, open-chain and cyclic ethers such astetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethyleneglycol, dimethyl ether or the like, halogenated hydrocarbons such asmethylene chloride, chloroform and 1,2-dichloroethane, acetonitrile anddimethylformamide.

The hydrolysis of compounds of formula Ib⁴ to the corresponding catecholderivatives in accordance with process variant g) can also be carriedout according to known methods which are familiar to any person skilledin the art. The hydrolysis can be carried out, for example, by treatmentwith an alkali metal hydroxide such as sodium hydroxide or potassiumhydroxide in a suitable solvent. Suitable solvents are, for example,lower alcohols such methanol and water or mixtures thereof. Thehydrolysis can be carried out, for example, in a temperature range ofabout 0° C. to the boiling temperature of the solvent. However, it ispreferably carried out at room temperature.

In accordance with process variant h) there can be prepared compounds ofthe formula ##STR20##

wherein Ra, Rb, R"' and R²³ have the above significance, and thecorresponding di-O-lower alkanoyl derivatives thereof. Cyclic aminessuch as pyrrolidine, piperidine, morpholine and thiomorpholine arepreferably used as the secondary amine. Suitable solvents for thisprocess are, for example, open-chain and cyclic ethers such astetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethyleneglycol and dimethyl ether, halogenated hydrocarbons such as methylenechloride, chloroform and 1,2-dichloroethane, acetonitrile anddimethylformamide. The reaction temperature conveniently lies in a rangeof about 0° C. to the boiling temperature of the chosen solvent. Thereaction is preferably carried out at room temperature. In an especiallypreferred embodiment the reaction is carried out in the presence of anacid, preferably a carboxylic acid such as acetic acid.

In accordance with process variant i) there can be prepared compounds ofthe formula ##STR21##

wherein Q⁵ is the group ##STR22##

and Ra, Rb, Re, Rf, A and n have the above significance. Suitablesolvents for this process are, for example, lower alcohols such asmethanol and ethanol, open-chain and cyclic ethers such astetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethyleneglycol and dimethyl ether, acetonitrile and dimethylformamide. Thereaction is preferably carried out at an elevated temperature, forexample in a range of about 50° C. to the boiling temperature of thechosen solvent. It is preferably carried out at the boiling temperatureof the chosen solvent.

In accordance with process variant j) there can be prepared compounds ofthe formula ##STR23##

wherein Ri is the group -COR³¹, an aromatic carbocyclic group, or anaromatic or partially unsaturated heterocyclic group attached via acarbon atom or an optionally substituted, saturated or partiallyunsaturated lower hydrocarbon residue and Ra, Rb, R³¹, R⁴, A, Z, n and phave the above significance.

This process can also be carried out according to known methods whichare familiar to any person skilled in the art. Suitable solvents are,for example, lower alcohols such as methanol and ethanol,dimethylformamide and water. The reaction is conveniently carried out atroom temperature.

In accordance with process variant k), the compounds of formula Ib canbe converted into ester or ether derivatives which are hydrolyzableunder physiological conditions. Suitable ester derivatives which arehydrolyzable under physiological conditions are especially the compoundsof formula Ib in which at least one of the two phenolic hydroxy groupsis acylated by a lower fatty acid. These can be prepared according toknown methods which are familiar to any person skilled in the art. In apreferred embodiment, the acylation is carried out with thecorresponding lower fatty acid anhydride in the presence of a catalyticamount of a strong acid, with excess fatty acid anhydride beingpreferably used as the solvent. Suitable acids are, for example,sulfuric acid and organic sulfonic acids such as p-toluenesulfonic acid.

Suitable ether derivatives which are hydrolyzable under physiologicalconditions are, for example, compounds of formula Ib in which at leastone of the two phenolic hydroxy groups is etherified by a lower1-alkoxycarbonyl-oxy-1-alkyl, lower 1-alkanoyloxy-1-alkyl or by a lower2-oxo-1-alkyl group. The etherification can be carried out according toknown methods which are familiar to any person skilled in the art. Forexample, a compound of formula Ib can be reacted with a lower1-alkoxycarbonyloxy-1-alkyl halide, a lower 1-alkanoyloxy-1-alkyl halideor a lower 2-oxo-1-alkyl halide, with this etherification beingconveniently carried out in the presence of a base. As halides therecome into consideration, in particular, the iodides. Suitable bases are,for example, alkali metal hydroxides and alkali metal carbonates such assodium hydroxide and sodium carbonate.

In accordance with process variant k), compounds of formula Ib above canalso be converted into pharmaceutically acceptable salts. As salts therecome into consideration, in particular, salts with pharmaceuticallyacceptable bases. As examples of such salts there are to be mentionedthe alkali metal salts such as the sodium and potassium salts. Thesesalts can be prepared according to known methods which are familiar toany person skilled in the art.

The various compounds which are used as starting materials are known orcan be prepared according to known methods. The Examples which followcontain detailed information concerning the preparation of the startingmaterials.

As mentioned earlier, the compounds of formula Ia inhibit the enzymeCOMT. This activity can be determined quantitatively as follows: Ratliver homogenate is incubated in the presence of a suitable substrate asdescribed in J. Neurochem. 38, 191-195 (1982) and the COMT activity ismeasured. In a second series of experiments the incubation is carriedout in the presence of a compound of formula Ia. The IC₅₀ can then becalculated from the difference of the COMT activity which is determined.IC₅₀ is given in nmol/l and is that concentration in the incubationmixture which is required to reduce the COMT activity by 50%. The IC₅₀values for some compounds of formula Ia are given in the followingTable. Moreover, this Table contains data concerning the acute toxicityof these compounds (LD₅₀ in mg/kg in the case of single oraladministration to mice).

    ______________________________________                                                                     LD.sub.50 in                                     Compound of formula Ia                                                                         IC.sub.50 in nmol/l                                                                       mg/kg p.o.                                       ______________________________________                                        3,4-Dihydroxy-5-nitrophenyl                                                                    53.4        1250-2500                                        2-pyridyl ketone                                                              3,4-Dihydroxy-5-nitrophenyl                                                                    47.0        1000-2000                                        3-pyridyl ketone                                                              3,4-Dihydroxy-5-nitrophenyl                                                                    67.0        1000-2000                                        4-pyridyl ketone                                                              n-Butyl 3,4-dihydroxy-5-                                                                       20.0        312-625                                          nitrobenzoate                                                                 n-Butyl 3,4-dihydroxy-5-                                                                       25.9        2500-5000                                        nitrocinnamate                                                                Ethyl 3,4-dihydroxy-5-                                                                         48.1        1250-2500                                        nitrophenylglyoxylate                                                         3,4-Dihydroxy-5-nitrobenzo-                                                                    48.0         500-1000                                        phenone                                                                       3,5-Dinitropyrocatechol                                                                        36.9         500-1000                                        2'-Fluoro-3,4-dihydroxy-5-                                                                     42.0        312-625                                          nitrobenzophenone                                                             ______________________________________                                    

The compounds of formula Ia, ester or ether derivatives thereof, andsalts thereof can be used as medicaments, for example, in the form ofpharmaceutical preparations for enteral or parenteral administration.The compounds of formula Ia can be administered, for example, perorally,for example in the form of tablets, coated tablets, dragees, hard andsoft gelatine capsules, solutions, emulsions or suspensions, rectally,for example, in the form of suppositories, or parenterally, for example,in the form of injection solutions.

The manufacture of the pharmaceutical preparations can be effected in amanner which is familiar to any person skilled in the art by bringingthe compounds of formula Ia, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, the usualpharmaceutical adjuvants.

As carrier materials there are suitable not only inorganic carriermaterials, but also organic carrier materials. Thus, for tablets, coatedtablets, dragees and hard gelatine capsules there can be used as carriermaterials, for example, lactose, maize starch or derivatives thereof,talc, stearic acid or its salts. Suitable carriers for soft gelatinecapsules are, for example, vegetable oils, waxes, fats and semi-solidand liquid polyols. Depending on the nature of the active substances nocarriers are, however, required in the case of soft gelatine capsules.Suitable carrier materials for the preparation of solutions and syrupsare, for example, water, polyols, saccharose, invert sugar and glucose.Suitable carrier materials for injection solutions are, for example,water, alcohols, polyols, glycerine and vegetable oils. Suitable carriermaterials for suppositories are, for example natural or hardened oils,waxes, fats and semi-liquid or liquid polyols.

As pharmaceutical adjuvants there come into consideration the usualpreserving agents, solubilizers, stabilizing agents, wetting agents,emulsifying agents, flavor-improving agents such as sweetening agentsand flavoring agents, coloring agents, salts for varying the osmoticpressure, buffers, coating agents and antioxidants.

The dosage of the compounds of formula Ia, ester or ether derivativesthereof and salts thereof can vary within wide limits depending on theillness to be treated, the age and the individual condition of thepatient and on the mode of administration and will, of course, be fittedto the individual requirements in each particular case. In theimprovement of the treatment of Parkinson's disease and of parkinsonismwith L-dopa a daily dosage of 25 mg to about 1000 mg, especially about100 mg to about 300 mg, comes into consideration. Depending on thedosage it is convenient to administer the daily dosage in several dosageunits.

The pharmaceutical preparations in accordance with the inventionconveniently contain about 25 mg to about 300 mg, preferably about 50 mgto about 150 mg, of a compound of formula Ia or of an ester or etherderivative thereof which is hydrolyzable under physiological conditionsor of a pharmaceutically acceptable salt thereof.

The Examples which follow further illustrate the invention. Alltemperatures are given in degrees Celsius.

EXAMPLE 1

a) 17.1 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde are treated with170 ml of constant-boiling hydrobromic acid and heated under reflux for3.5 hours. After cooling the separated precipitate is filtered undersuction, washed twice with ice-water and taken up in ethyl acetate. Theorganic phase is washed twice with 50 ml of sodium chloride solutioneach time, dried over magnesium sulfate and evaporated in a water-jetvacuum. The crystals obtained are taken up in methylene chloride,whereupon the solution is filtered over a ten-fold amount of silica gel.The material obtained is crystallized from ethyl acetate/isopropylether. There is obtained 3,4-dihydroxy-5-nitrobenzaldehyde in the formof yellow crystals of m.p. 142°-143°.

b) A solution of 1.7 g of hydroxylamine O-sulfonic acid in 6 ml of wateris added to a solution of 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde in25 ml of water, subsequently stirred at 65° for 3.5 hours, cooled, theseparated precipitate is filtered off under suction and taken up inethyl acetate. The organic phase is dried over sodium sulfate andevaporated in a water-jet vacuum. The crystals obtained arerecrystallized from ethyl acetate/n-hexane. There is obtained3,4-dihydroxy-5-nitrobenzonitrile in the form of yellow crystals of m.p.194°-195°.

EXAMPLE 2

aa) 10 ml of tert.butyl lithium solution (1.4M in hexane) are addeddropwise at -70° within 10 minutes to 4.1 g of4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 40 ml oftetrahydrofuran. After stirring at -70° for 2 hours. 1 ml ofpyridine-3-carbaldehyde is added within 5 minutes. The reaction mixtureis stirred at -70° for 1 hour and at 0° for 2 hours, and poured into 100ml of 1N hydrochloric acid. The mixture is extracted three times with 50ml of ether each time. The combined ether phases are washed with 100 mlof 1N hydrochloric acid and 20 ml of water. The combined aqueous phasesare made alkaline with aqueous ammonia solution and extracted threetimes with 100 ml of methylene chloride each time. The combinedmethylene chloride phases are dried over sodium sulfate and evaporated.There is obtained alpha-[4-(benzyloxy)-3-methoxyphenyl]-3-pyridinemethanol as an oil.

ab) In an analogous manner, using pyridine-4-carbaldehyde there isobtained alpha-[4-(benzyloxy)-3-methoxyphenyl]-4-pyridinemethanol as anoil.

ba) 3.2 g of alpha-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinemethanolsuspended in 50 ml of water are treated with 2.5 g of potassiumpermanganate, whereupon the mixture is stirred at 90° for 30 minutesAfter adding a further 1.0 g of potassium permanganate and stirring fora further 30 minutes at 90° the mixture is cooled to room temperatureand extracted twice with 150 ml of ethyl acetate each time. The combinedethyl acetate phases are washed with sodium chloride solution, driedover sodium sulfate and evaporated. The thus-obtained residue ischromatographed on 50 g of silica gel with ethyl acetate. Afterrecrystallization from methylene chloride/hexane there is obtained4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone of m.p. 76°.

bb) In an analogous manner, fromalpha-[4-(benzyloxy)-3-methoxyphenyl)-4-pyridinemethanol there isobtained 4-(benzyloxy)-3-methoxyphenyl 4-pyridyl ketone of m.p. 85°-87°(methylene chloride/hexane).

ca) 50 ml of 33 percent hydrobromic acid in acetic acid are addeddropwise within 15 minutes at 10° to 20 g of4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml ofmethylene chloride. After stirring at 20° for 3 hours, the reactionmixture is poured into a mixture of 100 ml of conc. aqueous ammonia andice. The pH is adjusted to 6 by adding acetic acid. The methylenechloride phase is separated; the aqueous phase is extracted twice morewith 100 ml of methylene chloride each time. The combined methylenechloride phases are dried over sodium sulfate and evaporated. Theresidue is recrystallized from methylene chloride/hexane. There isobtained 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone of m.p. 150°-151°.

cb) In an analogous manner, from 4-(benzyloxy)-3-methoxyphenyl 4-pyridylketone there is obtained 4-hydroxy-3-methoxyphenyl 4-pyridyl ketone ofm.p. 215°-218° (acetonitrile).

da) 0.38 ml of 65 percent nitric acid is added dropwise at roomtemperature to 1.15 g of 4-hydroxy-3-methoxyphenyl 3-pyridyl ketonedissolved in 15 ml of acetic acid. After stirring for 2 hours, thereaction mixture is poured into 120 ml of ice-water, whereupon themixture is adjusted to pH 5 with conc. ammonia and the precipitateformed is filtered off. The thus-obtained residue is heated under refluxin 20 ml of acetonitrile, whereupon it is again filtered off. There isobtained 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl ketone as browncrystals of m.p. 193°.

db) In an analogous manner, from 4-hydroxy-3-methoxyphenyl 4-pyridylketone there is obtained 4-hydroxy-3-methoxy-5-nitrophenyl 4-pyridylketone of m.p. 240°.

e) 3.5 g of 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl ketone dissolvedin 70 ml of 48 percent aqueous hydrobromic acid are stirred at 100° for18 hours. The reaction mixture is subsequently evaporated under reducedpressure. The residue is recrystallized from water. There is obtained3,4-dihydroxy-5-nitrophenyl 3-pyridyl ketone hydrobromide of m.p. 265°.

f) In an analogous manner, from 4-hydroxy-3-methoxy-5-nitrophenyl4-pyridyl ketone there is obtained 3,4-dihydroxy-5-nitrophenyl 4-pyridylketone of m.p. 246° (from water).

g) 13.2 g of 3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketone are suspendedin 500 ml of methanol and treated while stirring with 4.88 g ofmethanesulfonic acid. The suspension is heated under reflux for 60minutes. It is subsequently cooled to 10°, the crystals are filteredunder suction and washed twice with 30 ml of methanol each time. Thereis obtained 3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketonemethanesulfonate of m.p. 260°-261° (dec.).

EXAMPLE 3

a) A solution of 2.6 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 26ml of constant-boiling hydrobromic acid is heated under reflux for 2hours. After cooling the solvent is distilled in a water-jet vacuum. Thecrystalline residue is recrystallized from 50 ml of water at boilingtemperature. There is obtained 3,4-dihydroxy-5-nitrobenzoic acid in theform of yellow crystals of m.p. 224°-226°.

b) 1.0 g of 3,4-dihydroxy-5-nitrobenzoic acid is treated with 20 ml ofmethanolic hydrochloric acid, stirred at 45° for 3 hours and, afterremoving the solvent, the residue is taken up in methylene chloride. Theorganic phase is washed with sodium chloride solution, dried over sodiumsulfate and evaporated. The crystalline product obtained is taken up inmethylene chloride and filtered over a ten-fold amount of silica gel.The material obtained is recrystallized from ethyl acetate/n-hexane.There is obtained methyl 3,4-dihydroxy-5-nitrobenzoate in the form ofyellow crystals of m.p. 144°-145°.

The following esters are obtained in an analogous manner starting from3,4-dihydroxy-5-nitrobenzoic acid:

c) Ethyl 3,4-dihydroxy-5-nitrobenzoate of m.p. 106°-107° (from ethylacetate/n-hexane),

d) n-butyl 3,4-dihydroxy-5-nitrobenzoate of m.p. 73°-74° (from methylenechloride) and

e) n-hexyl 3,4-dihydroxy-5-nitrobenzoate of m.p. 44°-45° (from isopropylether).

EXAMPLE 4

a) 25 ml of 2M phenyl lithium solution (in benzene/ether (7:3)) areadded dropwise within 15 minutes to 10.0 g of3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of tetrahydrofuranand the mixture is stirred at 0° for 1 hour and at 20° for 2 hours. Themixture is subsequently treated with 150 ml of 2N sulfuric acid andextracted three times with 150 ml of ether. The combined ether phasesare washed with sodium chloride solution, dried over sodium sulfate andevaporated. The thus-obtained residue is chromato graphed on 180 g ofsilica gel with methylene chloride. There is obtained3,4-dimethoxy-5-nitrobenzhydrol as an amorphous solid.

b) 2.5 g of 3,4-dimethoxy-5-nitrobenzhydrol dissolved in 50 ml ofmethylene chloride are treated with 2.2 g of pyridinium chlorochromate,whereupon the mixture is stirred at room temperature for 2 hours. Theinsoluble constituents are subsequently filtered. The filtrate isevaporated and the residue is chromatographed on 60 g of silica gel withmethylene chloride. After crystallization from methylene chloride/hexanethere is obtained 3,4-dimethoxy-5-nitrobenzophenone of m.p. 78°-80°.

c) 0.5 g of 3,4-dimethoxy-5-nitrobenzophenone is stirred at 110° for 30hours in a mixture of 4 ml of acetic acid and 4 ml of 48 percent aqueoushydrobromic acid. The reaction mixture is subsequently evaporated todryness. The residue is taken up in methylene chloride. It is washedwith water, dried over sodium sulfate and evaporated. Afterrecrystallization from methylene chloride/hexane there is obtained3,4-dihydroxy-5-nitrobenzophenone of m.p. 132°.

EXAMPLE 5

a) 4.9 g of magnesium are suspended in 15 ml of absolute ethanol and,after adding 1 ml of carbon tetra- chloride, warmed until the reactionstarts. A solution of 31.8 g of diethyl malonate in 19.9 ml of absoluteethanol and 80 ml of absolute toluene is then added dropwise whilestirring so that the temperature lies between 50° and 60°. The reactionmixture is subsequently stirred at this temperature for an additional 1hour, whereupon it is cooled to -5° and a solution of 49.3 g of3,4-dimethoxy-5-nitrobenzoyl chloride (m.p. 82°-85°) in 300 ml ofabsolute toluene and 50 ml of absolute tetrahydrofuran is added dropwiseso that the temperature does not exceed -5°. The mixture is subsequentlystirred at room temperature overnight. After distillation of the solventthe residue is dissolved in 500 ml of ethyl acetate. The solution istreated while stirring and cooling with ice with an ice-cold solution of12 ml of concentrated sulfuric acid in 80 ml of water. The organic phaseis washed with sodium chloride solution, dried over magnesium sulfateand evaporated. The oil obtained is chromatographed on a ten-fold amountof silica gel with methylene chloride. The crystalline material obtainedis recrystallized from isopropyl ether. There is obtained diethyl3,4-dimethoxy-5-nitrobenzoylmalonate in the form of pale beige crystalsof m.p. 70°.

b) 19.0 g of diethyl 3,4-dimethoxy-5-nitrobenzoylmalonate are dissolvedin 100 ml of glacial acetic acid, 5 drops of concentrated sulfuric acidare added thereto and the mixture is heated under reflux for 16 hours.The acetic acid is distilled at 60° in a water-jet vacuum and theresidue is treated three times with 250 ml of toluene each time, wherebyit is evaporated each time. The crystalline residue is extracted withethyl acetate. The organic phase is washed with water, dried overmagnesium sulfate and evaporated. The crystals obtained arechromatographed on a 30-fold amount of silica gel with toluene. Thecrystalline material obtained is recrystallized from isopropyl ether.There is obtained 3,4-dimethoxy-5'-nitroacetophenone in the form ofyellowish crystals of m.p. 86°-87°.

c) 2 g of 3',4'-dimethoxy-5'-nitroacetophenone are treated with 30 ml ofconstant-boiling hydrobromic acid and stirred at 140° for 2.5 hours.After cooling the mixture is poured into 200 ml of ice-water andextracted three times with 100 ml of ethyl acetate each time. Theorganic phase is washed twice with 25 ml of sodium chloride solutioneach time, dried over sodium sulfate and evaporated. The productobtained is filtered with ethyl acetate over a 20-fold amount of silicagel. By recrystallization of the material obtained from water there isobtained 3',4'-dihydroxy-5'-nitroacetophenone in the form of yellowcrystals of m.p. 159°-160°.

The same compound is obtained starting from4'-hydroxy-3'-methoxy-5'-nitroacetophenone by treatment with hydrobromicacid at the boiling temperature.

EXAMPLE 6

a) 100 g of guaiacol are dissolved in 136.4 g of isobutyric anhydride,treated with 120 g of anhydrous zinc chloride (whereby all passes intosolution), the reaction mixture is heated to 155° and cooled after threeminutes. The residue is first subjected to a steam distillation in orderto remove readily volatile constituents and is then extracted threetimes with 500 ml of ether each time. The organic phase is washed twicewith 250 ml of water each time, once with 150 ml of saturatedbicarbonate solution and again with 250 ml of water, dried over sodiumsulfate and evaporated in a water-jet vacuum. The brown resin obtainedis distilled in a high vacuum. The distillate of b.p. 105°-120° (6.67Pa) is dissolved in ether, whereupon the solution is treated withn-hexane until crystallization begins. The crystals obtained arerecrystallized from ether/hexane. There is obtained4'-hydroxy-3'-methoxy-2-methyl-propiophenone in the form of colorlesscrystals of m.p. 86°-87°.

b) 15.0 g of 4'-hydroxy-3'-methoxy-2-methyl-propiophenone are dissolvedin 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid(11.2N) in 40 ml of glacial acetic acid are added dropwise thereto whilestiring within 15 minutes. After 15 minutes the reaction mixture ispoured into ice-water and the separated crystals are filtered undersuction, washed with water and dissolved in methylene chloride. Thesolution is dried over sodium sulfate and evaporated. The crude productobtained is taken up in methylene chloride and filtered over 100 g ofsilica gel. The thus-obtained crystals are recrystallized from methylenechloride/n-hexane. There is obtained4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone in the form ofyellow crystals of m.p. 85°-87°.

c) 8.0 g of 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone aretreated with 64 g of pyridine hydrochloride and stirred at 180° for 45minutes. After cooling the reaction mixture is poured into 500 ml ofice-water, whereupon it is made acid with 20 ml of 3N hydrochloric acidand extracted with methylene chloride. The organic phase is washed withwater, dried over sodium sulfate and evaporated in a water-jet vacuum.After crystallization from methylene chloride/n-hexane there is obtained3',4'-dihydroxy-2-methyl-5'-nitropropiophenone in the form of yellowcrystals of m.p. 98°-99°.

EXAMPLE 7

a) 100 g of guaiacol are dissolved in 136.4 g of butyric anhydride,treated with 120 g of zinc chloride, heated for 3 minutes as given inExample 6.a and then worked-up as described there. The crude productobtained after high vacuum distillation is chromatographed with tolueneon 600 g of silica gel. After recrystallization from ether/n-hexanethere is obtained 4'-hydroxy-3'-methoxy-butyrophenone in the form ofcolorless crystals of m.p. 40°-41°.

b) 6.5 ml of 11.2N nitric acid are added dropwise to a solution of 12.7g of 4'-hydroxy-3'-methoxybutyrophenone in 250 ml of glacial acetic acidwhile stirring within 10 minutes. The reaction mixture is subsequentlystirred for 15 minutes, poured into ice-water, the separated precipitateis filtered under suction, washed with ice-water and taken up inmethylene chloride. The methylene chloride solution is filtered over 50g of silica gel. The material obtained is recrystallized from methylenechloride/n-hexane. There is obtained4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone in the form of yellowcrystals of m.p. 92°-93°.

c) 10.2 g of 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone are treatedwith 80 g of pyridine hydrochloride and stirred at 200° for 40 minutes.After cooling the reaction mixture is poured into 500 ml of ice-water.The mixture is treated with 30 ml of 3N hydrochloric acid and extractedwith methylene chloride. The organic phase is dried over sodium sulfateand evaporated. The crude product obtained is chromatographed withmethylene chloride on 150 g of silica gel. The material obtained isrecrystallized from methylene chloride/n-hexane. There is obtained3',4'-dihydroxy-5'-nitrobutyrophenone in the form of yellow crystals ofm.p. 88°-90°.

EXAMPLE 8

a) 2.25 g of 3,4-dihydroxy-5-nitrocinnamic acid are dissolved in 50 mlof methanol and hydrochloric acid gas is introduced into this solutionfor 10 minutes. After 1 hour 50 ml of isopropyl ether are added thereto,and the separated precipitate is filtered under suction and washed withisopropyl ether. After recrystallization from methanol/ether there isobtained methyl 3,4-dihydroxy-5-nitrocinnamate in the form of yellowcrystals of m.p. 186°-187°.

b) In an analogous manner, from 3,4-dihydroxy-5-nitrocinnamic acid andbutanolic hydrochloric acid solution there is obtained n-butyl3,4-dihydroxy-5-nitrocinnamate in the form of yellowish crystals of m.p.129°-130°.

EXAMPLE 9

5.0 g of diethyl 3,4-dimethoxy-5-nitrobenzoyl malonate are dissolved in50 ml of absolute methylene chloride. After cooling to -20° a solutionof 16.9 g of boron tribromide in 30 ml of methylene chloride is addeddropwise thereto while stirring so that the temperature does not exceed-20°. The mixture is subsequently stirred at room temperature overnight.After adding 80 ml of ethanol the mixture is stirred at room temperaturefor 30 minutes and the solvent is subsequently distilled in a water-jetvacuum. The residue is treated with water and extracted with methylenechloride. The organic phase is washed with water, dried over sodiumsulfate and evaporated. The crude product obtained is filtered withethyl acetate over 50 g of silica gel. The crystalline residue obtainedis recrystallized from methylene chloride/n-hexane. There is obtainedethyl 3,4-dihydroxy-5-nitro-benzoylacetate in the form of yellowcrystals of m.p. 141°-142°.

EXAMPLE 10

a) A solution of 1.49 g of 2-phenylethylamine in 100 ml of methylenechloride is treated with 1.26 g of triethylamine. A solution of 3.0 g of3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of methylene chloride isadded dropwise thereto while stirring, whereupon the mixture is stirredfor a further 15 minutes. The organic phase is then extracted twice with50 ml of ice-water each time, dried over sodium sulfate and evaporatedin a water-jet vacuum. After recrystallization from methylenechloride/n-hexane there is obtained3,4-dimethoxy-5-nitro-N-phenethylbenzamide in the form of pale beigeneedles of m.p. 121°-122°.

b) 3.6 g of 3,4-dimethoxy-5-nitro-N-phenethylbenzamide are heated underreflux with 36 ml of phosphorus oxychloride under a nitrogen atmospherefor 96 hours. After distilling the excess phosphorus oxychloride in awater-jet vacuum at 60°, the residue is treated three times with 100 mlof toluene each time, with the solvent being distilled each time. Theresidue is taken up in methylene chloride. The organic phase is washedwith water, dried over sodium sulfate and evaporated in a water-jetvacuum. The red resin obtained is chromatographed on 120 g of silica gelwith methylene chloride/ethyl acetate (1:1). There is obtained1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline in the form of ayellow resin.

c) 1.4 g of 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline aretreated with 15 ml of constant-boiling hydrobromic acid and heated toboiling under reflux under a nitrogen atmosphere for 1.5 hours. Afterdistilling the hydrobromic acid in a water-jet vacuum, the crystallineresidue is recrystallized from acetone. There is obtained5-(3,4-dihydro-1-isoquinolinyl)-3-nitropyrocatechol hydrobromide in theform of yellow crystals of m.p. >250° (decomposition).

EXAMPLE 11

a) 5.0 g of 4-hydroxy-5-methoxy-isophthalaldehyde are treated with 50 mlof constant-boiling hydrobromic acid and heated to boiling under refluxand while stirring under an argon atmosphere for 3 hours. After cooling50 ml of ice-water are added thereto, and the separated precipitate isfiltered under suction and washed with water. The crude product is takenup in ethyl acetate and filtered over 50 g of aluminum oxide (activitygrade II). The crystalline material obtained is recrystallized fromethyl acetate/n-hexane. There is obtained 4,5-dihydroxyisophthalaldehydein the form of slightly orange crystals of m.p. 201°-202°.

b) A solution of 3.27 g of hydroxylamine O-sulfonic acid in 12 ml ofwater is added dropwise at 30° while stirring to a solution of 2.0 g of4,5-dihydroxyisophthalaldehyde in 20 ml of water, whereupon the mixtureis held at 65° for 10 hours. After cooling the separated precipitate isfiltered under suction, washed with water and taken up in ethyl acetate.The organic phase is washed with water, dried over sodium sulfate andevaporated in a water-jet vacuum. After recrystallization from ethylacetate there is obtained 4,5-dihydroxyisophthalonitrile in the form ofyellow crystals which decompose above 300°.

EXAMPLE 12

a) A solution of 38 g of fuming nitric acid (96%) in 50 ml of glacialacetic acid is added dropwise while stirring and within 30 minutes at20°-25° to a solution of 112.5 g of2-bromo-4'-hydroxy-3'-methoxyacetophenone in 560 ml of glacial aceticacid. Yellow-brown crystals thereby separate. After 90 minutes thereaction mixture is poured on to 300 g of ice. The crystals are filteredunder suction, washed with 1000 ml of water and dissolved in 1000 ml ofmethylene chloride. The organic phase is washed with saturated sodiumchloride solution, dried over sodium sulfate, filtered and the filtrateis evaporated at 50° in a water-jet vacuum until crystallization begins.The crystallizate, cooled to room temperature, is removed by filtrationunder suction and washed with a small amount of methylene chloride.There is obtained 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone ofm.p. 147°-149°.

b) Method A:

ba) A suspension of 580.1 mg of2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 10 ml of ethanolis treated with 443.8 mg of selenium dioxide and heated under reflux for71 hours. Thereafter, the selenium is removed by filtration and thefiltrate is evaporated. The residue is dissolved in methylene chloride,washed with saturated sodium chloride solution, dried over sodiumsulfate, filtered and evaporated. There is obtained ethyl4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 165°-167° (fromethanol).

In an analogous manner:

bb) From 2-bromo-440-hydroxy-3'-methoxy-5'-nitroacetophenone andn-butanol there is obtained n-butyl4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 105°-107° (fromethanol) and

bc) from 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone andn-hexanol there is obtained hexyl4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 103°-105° (fromn-hexanol/petroleum ether).

c) Method B:

ca) A suspension of 29.01 g of2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 300 ml oftert.butanol is treated with 27.74 g of selenium dioxide and heated toboiling under reflux for 18 hours. The hot reaction mixture is suctionfiltered through a filter aid of diatomaceous earth while rinsing withmethylene chloride. The filtrate is evaporated and the residue issuspended in 150 ml of hot methylene chloride. The crystallineprecipitate is filtered under suction and washed with a small amount ofmethylene chloride. There is obtained4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid of m.p. 169°-171°.

2.42 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid are dissolvedin 25 ml of dry N,N-dimethylformamide, treated at room temperature with50 mg of 4-dimethylaminopyridine and 920 mg of dry methanol,subsequently cooled to 0° with an ice-bath and 2.27 g ofN,N-dicyclohexylcarbodiimide are added thereto. After 10 minutes theice-bath is removed and the reaction mixture is stirred for a further 1hour at room temperature. The mixture is subsequently evaporated. Theresidue is dissolved in ethyl acetate, whereupon insoluble urea isfiltered, the filtrate is washed four times with water, dried oversodium sulfate, filtered and evaporated. There is obtained methyl4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 155°-157° (frommethylene chloride/ether).

In an analogous manner:

cb) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid and ethanolthere is obtained ethyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxlate ofm.p. 165°-167° (from ethanol) and

cc) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid and isopropanolthere is obtained i-propyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylateof m.p. 99°-101° (from isopropanol).

d) A suspension of 17.2 g of ethyl4-hydroxy-3-methoxy-5-nitrophenylglyoxylate in 100 ml of dryacetonitrile and 100 ml of dry toluene is treated with 10.53 g of sodiumiodide and 11.9 g of silicon tetrachloride and heated under reflux for47 hours. The reaction mixture is then evaporated and the residue isdistilled six times with 200 ml of toluene each time. The residueobtained is partitioned between water and ether and filtered through afilter aid of diatomaceous earth. The ethereal phase is washed fourtimes with saturated sodium chloride solution, dried over sodiumsulfate, filtered and evaporated. The oily residue is treated threetimes with ether and active carbon. There is obtained ethyl3,4-dihydroxy-5-nitrophenylglyoxylate of m.p. 77°-79° (fromether/n-hexane).

In an analogous manner:

e) From methyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate there isobtained methyl 3,4-dihydroxy-5-nitrophenylglyoxylate as a yellowdistillate at 145°-150° and 10.67 Pa,

f) from isopropyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate there isobtained isopropyl 3,4-dihydroxy-5-nitrophenylglyoxylate as a yellowdistillate at 155°-160° and 12.0 Pa,

g) from n-butyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate there isobtained n-butyl 3,4-dihydroxy-5-nitrophenylglyoxylate as a yellowdistillate at 160°-165° and 10.67 Pa and

h) from n-hexyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate there isobtained hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate as a yellowdistillate at 165°-170° and 12.0 Pa.

EXAMPLE 13

236.1 mg of n-hexyl 3,4-dihydroxy-nitrophenylglyoxylate are dissolved in15 ml of ethanol and treated with 7.59 ml of 0.1N sodium hydroxidesolution. After 1 hour the reddish-yellow solution is evaporated. Theresulting sodium salt of the n-hexyl3,4-dihydroxy-5-nitrophenylglyoxylate is crystallized from water and hasa m.p. of ˜300°.

EXAMPLE 14

A solution of 3.18 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate in47.5 ml of ethanol is treated with 1.11 g of O-methylhydroxylaminehydrochloride, 1.95 g of sodium acetate and 2.5 ml of water and heatedto boiling under reflux for 5 hours. Thereafter, the reaction mixture isevaporated and the residue is treated with ether and water. The organicphase is washed with saturated sodium chloride solution, dried oversodium sulfate, filtered and evaporated. The residue is chromatographedon silica gel with methylene chloride. There is obtained a 7:3 mixtureof n-hexyl E- and Z-3,4-dihydroxy-5-nitrophenylglyoxylate O-methyl oximeas a reddish oil: 80 MHz NMR spectrum (CDCl₃): signal for O-methyl at3.96 and 4.05 ppm.

EXAMPLE 15

A solution of 5.1 g of ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate indry methylene chloride is treated dropwise at -10° within 15 minuteswith 25 g of boron tribromide. The mixture is then stirred at -10° for 1hour and subsequently at room temperature for 17 hours. Thereafter, thereaction mixture is evaporated, the residue is treated cautiously withwater and stirred at 50° for an additional 30 minutes. After cooling toroom temperature, the flocculent precipitate is filtered under suction.The aqueous phase is acidified with 10 ml of 1N hydrochloric acid,extracted four times with ether, the combined organic extracts arewashed four times with saturated sodium chloride solution, dried oversodium sulfate, filtered and evaporated. The crude product is filteredthree times in succession in ether through a filter aid of diatomaceousearth. There is obtained 3,4-dihydroxy-5-nitrophenylglyoxylic acid ofm.p. 172°-174° (from isopropyl ether).

EXAMPLE 16

a) A mixture of 3.93 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylateand 1.38 g of 2-aminophenol is melted at 120° while stirring. The meltcrystallizes after 5 minutes. After 2 hours it is cooled andrecrystallized from methanol. There is obtained3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one of m.p.202°-204°.

In an analogous manner:

b) From n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and2-amino-p-cresol there is obtained3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin -2-one ofm.p. 233°-235° (from methanol/methylene chloride),

c) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and2-amino-4-propylphenol there is obtained3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-1,4-benzoxazin-2-one of m.p.200°-202° (from methanol),

d) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and3-amino-4-hydroxybenzoic acid there is obtained3-(3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-1,4-benzoxazine-6-carboxylicacid of m.p. 286°-287° (from acetone/petroleum ether),

e) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and2-amino-4-chlorophenol there is obtained6-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one of m.p.241°-243° (from methanol),

f) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and2-amino-4,6-dichlorophenol there is obtained6,8-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2H-1, 4-benzoxazin-2-one ofm.p. 237°-239° (from ethanol/ether) and

g) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and2-amino-5-nitrophenol there is obtained3-(3,4-dihydroxy-5-nitrophenyl)-7-nitro-2H-1,4-benzoxazin-2-one of m.p.253°-255° (from acetonitrile/ethanol).

EXAMPLE 17

a) A mixture of 396.0 mg of n-hexyl3,4-dihydroxy-5-nitrophenylglyoxylate and 137.6 mg of1,2-phenylenediamine is heated to 120° for 60 minutes. Thereafter, themixture is suspended in methanol, filtered under suction andrecrystallized from N,N-dimethylformamide/water. There is obtained3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p. >300°.

In an analogous manner:

b) From n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate andN-methyl-1,2-phenylene diamine there is obtained1-methyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H) -quinoxalinone of m.p.271°-273° (from methanol),

c) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate andN-Propyl-1,2-phenylene diamine there is obtained1-propyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H) -quinoxalinone of m.p.183°-185° (from methanol),

d) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and4,5-dimethyl-1,2-phenylenediamine there is obtained3-(3,4-dihydroxy-5-nitrophenyl)-6,7-dimethyl-2(1H)-quinoxalinone ofm.p. >300° (from N,N-dimethylformamide/water),

e) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and4,5-dichloro-1,2-phenylenediamine there is obtained6.7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone ofm.p. >300° (from N,N-dimethylformamide/water),

f) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and3-chloro-5-trifluoromethyl-1,2-phenylenediamine there is obtained a 1:1mixture of 8(and 5)-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-6 (and7)-trifluoromethyl-291H)-quinoxalinone of m.p. >300° (fromN,N-dimethylformamide/water),

g) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and4-methoxy-1.2-phenylenediamine there is obtained a 1:1 mixture of3-(3,4-dihydroxy-5-nitrophenyl)-6(and 7)-methoxy-2(1H)-quinoxalinone ofm.p. >300° (from ethanol/ether),

h) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and4-nitro-1,2-phenylenediamine there is obtained 1:1 mixture of3-(3,4-dihydroxy-5-nitrophenyl)-6(and 7)-nitro-2(1H)-quinoxalinone ofm.p. >300° (from N,N-dimethylformamide/water) and

i) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate andN-hexyl-1,2-phenylenediamine there is obtained1-hexyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p.152°-154 (from methanol).

EXAMPLE 18

A solution of 1.07 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylateand 696.3 mg of 2,3-diaminonaphthalene in 3 ml of 1-hexanol is heated toboiling under reflux for 3 hours. The reaction mixture is then cooledand diluted with methanol. The crude product is filtered under suctionand recrystallized from N,N-dimethylformamide/water. There is obtained3-(3,4-dihydroxy-5-nitrophenyl)-benzo[g]quinoxalin-2(1H)-one of m.p.>300°.

EXAMPLE 19

A suspension of 2.05 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylateand 600.8 mg of thiosemicarbazide is stirred intensively at 90° for 30minutes. The mixture is then cooled to 40° and treated with a solutionof 870.1 mg of sodium hydroxide in 15 ml of water. The solution issubsequently heated to 90° for 30 minutes, cooled to room temperatureand treated dropwise with 2 ml of conc. hydrochloric acid. Thecrystallized-out product is filtered under suction and then dissolved inethyl acetate. The solution is washed with saturated sodium chloridesolution, dried over sodium sulfate, filtered and evaporated. There isobtained 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one of m.p. 282°-284° (from ethanol).

EXAMPLE 20

aaa) A suspension of 2.9 g of2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 761.2 mg ofthiourea in 170 ml of ethanol is treated at 60° with 820.3 mg of sodiumacetate and stirred for 6 hours. The reaction mixture is thenevaporated, the residue is treated with 170 ml of water and heated to60° for 30 minutes. After cooling the product is filtered under suctionand washed with water. There is obtained4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol of m.p. 248°-250° (fromethanol).

In an analogous manner:

aab) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone andN-phenylthiourea there is obtained4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol of m.p. 185°-187°(from ether).

aba) 50 ml of 1,2-dichloroethane and 3.56 g of calcium carbonate areadded to a solution of 4.88 g of 6-amino-4'-(trifluoromethyl)-hexanilidehydrochloride in 70 ml of water. The suspension is treated within 60minutes while stirring at room temperature with a solution of 2.6 g ofthiophosgene in 1.7 ml of toluene. After 16 hours the precipitate isremoved by filtration under suction and the organic phase is washed with1N hydrochloric acid and water. After drying over sodium sulfate andfiltration the filtrate is evaporated. There is obtained crude4'-(trifluoromethyl)hexananilide-6-isothiocyanate.

abb) A solution of 5.2 g of crude4'-(trifluoromethyl)hexananilide-6-isothiocyanate in 60 ml of ethanol istreated with 100 ml of conc. ammonia solution. After 30 minutes thereaction mixture is evaporated. The residue is dissolved in ethylacetate, washed with water, dried over sodium sulfate, filtered andevaporated. There is obtained1-[5-[(α,α,α-trifluoro-p-tolyl)carbamoyl]pentyl]-2-thiourea of m.p.140°-142° (from ethanol).

abc) A suspension of 666.7 mg of1-[5-[α,α,α-trifluoro-p-tolyl)carbamoyl]pentyl]-2-thiourea and 580.2 mgof 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 50 ml ofethanol is treated at 60° with 164.2 mg of sodium acetate. Areddish-yellow solution thereby results. After 90 minutes the reactionmixture is evaporated, the residue is treated with water, theprecipitate is filtered under suction and washed four times with 10 mlof water each time. There is obtained6-[[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-thiazolyl]amino]-4'-(trifluoromethyl) hexananilide of m.p. 160°-162°(from ethanol).

ac) A solution of 29.0 g of2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 13.5 g of2-aminoacetophenone in 250 ml of dry N,N-dimethylformamide is stirred at90° for 16 hours. The reaction mixture is then evaporated to about twothirds and poured on to ice. The separated crystals are filtered undersuction and dissolved in methylene chloride. The solution is washed withsaturated sodium chloride solution, dried over sodium sulfate, filteredand evaporated. There is obtained2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindole of m.p. 195°-197°(from methylene chloride/methanol).

ada) A suspension of 14.5 g of2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 5.41 g of1,2-phenylenediamine in 350 ml of methanol is treated with 4.92 g ofsodium acetate and the mixture is heated to boiling under reflux for 22hours. The reaction mixture is then evaporated, the residue is dissolvedin methylene chloride, this solution is washed four times with water,dried over sodium sulfate, filtered and evaporated. There is obtained2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline of m.p. 195°-197° (frommethylene chloride/methanol).

In an analogous manner:

adb) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and4,5-dimethyl-1,2-phenylenediamine there is obtained6,7-dimethyl-2-(4-hydroxy-3-methoxy-5 -nitrophenyl)quinoxaline of m.p.207°-209° (from methylene chloride/methanol).

b) A suspension of 267.3 mg of4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol in 10 ml of drymethylene chloride is treated at -20° with 1.25 g of boron tribromide.After the addition the mixture is stirred at -20° for a further 1 hourand at room temperature without cooling for 18 hours. The reactionmixture is then evaporated, the residue is treated cautiously with waterand stirred at 50° for 30 minutes. After cooling to room temperature themixture is suction filtered and the crude product is removed byfiltration and washed with a small amount of water. There is obtained5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide of m.p.244°-246° (from methanol).

In an analogous manner:

c) From 4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol there isobtained 5-(2-anilino-4-thiazolyl)-3-nitropyrocatechol of m.p. 202°-204°(from methanol),

d) from6-[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-thiazolyl)amino]-4'-(trifluoromethyl)hexananilide there is obtained6-[[4-(3,4-dihydroxy-5-nitrophenyl)-2-thiazolyl]amino]-4'-(trifluoromethyl)hexananilide of m.p. 214°-216° (from methanol),

e) from 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindole there isobtained 5-bromo-2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole of m.p.265°-267° (from methanol),

f) from 2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline there isobtained 2-(3,4-dihydroxy-5-nitrophenyl)-quinoxaline of m.p. 241°-243°(from methanol) and

g) from 6,7-dimethyl-2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxalinethere is obtained6,7-dimethyl-2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline of m.p.274°-276° (from methanol).

EXAMPLE 21

A mixture of 3.12 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and849.3 mg of thioacetamide are heated to boiling under reflux for 18hours in 40 ml of ethanol. After cooling, the crystals are filteredunder suction and recrystallized from methanol/isopropanol. There isobtained 5-(2-methyl-4-thiazolyl)-3-nitropyrocatechol hydrobromide ofm.p. 280°-282°.

EXAMPLE 22

A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and461 mg of thiosemicarbazide in 20 ml of n-butanol is heated to boilingunder reflux for 60 minutes. After cooling to room temperature thecrystals are filtered under suction and recrystallized from n-butanol.There is obtained5-(2-amino-6H-1,3,4-thiadiazin-5-yl)-3-nitropyrocatechol hydrobromide ofm.p. 265°-267°.

EXAMPLE 23

A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and505.7 mg of 2-amino-1,3,4-thiadiazole in 25 ml of n-butanol is heated toboiling under reflux for 7 hours. The reaction mixture is then cooled toroom temperature and the separated crystals are filtered under suction.There is obtained5-(imidazo-[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitropyrocatechol of m.p.278°-280° (from methanol).

EXAMPLE 24

A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone,1.01 g of 2-aminothiazole and 40 ml of ethanol is heated to boilingunder reflux for 23 hours. The reaction mixture is then cooled to roomtemperature and the crystals are removed by filtration under suction.There is obtained 5-(imidazo[2,1-b]thiazol-6-yl)-3-nitropyrocatecholhydrobromide of m.p. 286°-28820 (from methanol).

EXAMPLE 25

A mixture of 1.95 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone,1.06 g of 2-aminobenzothiazole and 50 ml of ethanol is heated to boilingunder reflux for 17 hours. The reaction mixture is then cooled to roomtemperature, whereupon the crystals are removed by filtration undersuction. There is obtained5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitropyrocatechol of m.p.303°-305° (from N,N-dimethylformamide/methanol).

EXAMPLE 26

A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone,1.51 g of 2-aminothiophenol and 50 ml of ethanol is heated to boilingunder reflux for 1 hour. The reaction mixture is then cooled to roomtemperature, whereupon the crystals are removed by filtration undersuction. There is obtained5-(2H-1,4-benzothiazin-3-yl)-3-nitropyrocatechol of m.p. 302'-304° (fromN,N-dimethylformamide/methanol).

EXAMPLE 27

A mixture of 987.5 mg of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenoneand 1.01 g of 2-aminopyridine is melted at 110°. After 30 minutes themelt is treated with 15 ml of ethanol and heated to boiling under refluxfor 3 hours. The reaction mixture is then cooled to room temperature andthe crystals are removed by filtration under suction. There is obtained5-(imidazo[1,2-a]pyridin-3-yl)-3-nitropyrocatechol of m.p. 250°14 252°(from N,N-dimethylformamide/methanol).

EXAMPLE 28

a) 8.9 g of 1,1'-carbonyldiimidazole are added to a solution of 10.7 gof 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of drytetrahydrofuran and the reaction mixture is subsequently heated to65°-70° for 5 hours. It is then cooled to room temperature and asolution of 21.6 g of 6-aminohexyl-t-butylcarbamate in 50 ml of drytetrahydrofuran is added dropwise thereto within 15 minutes. Thereaction mixture is then heated to 65°-70° for 18 hours, evaporated, theresidue is suspended in ethyl acetate, suction filtered and the suctionfiltered material is chromatographed on silica gel withacetone/methylene chloride (3:1). There is obtained[6-(4-hydroxy-5-nitro-m-anisamido)hexyl]-t-butylcarbamate of m.p.145°-147° (from isopropanol).

b) 5.8 ml of hydrobromic acid in glacial acetic acid (-33 percent) areadded at room temperature to a solution of 4.1 g of[6-(4-hydroxy-5-nitro-m-anisamido)-hexyl]-t-butylcarbamate in 80 ml ofglacial acetic acid. The mixture is stirred for 2 hours, the separatedcrystals are removed by filtration under suction and washed with ether.There is obtained N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamidehydrobromide of m.p. 207°-209° (from isopropanol).

c) 1.25 g of boron tribromide are added -20° to a suspension of 392.3 mgof N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamide hydrobromide in 25 mlof dry methylene chloride. After the addition the mixture is stirred at-20° for 1 hour and subsequently at room temperature for 17 hours. Thereaction mixture is then evaporated, the residue is treated with 10 mlof water and stirred at room temperature for 1 hour. After evaporatingthe water the residue is chromatographed on Sephadex LH 20 withtoluene/ethanol (1:1). There is obtainedN-6-aminohexyl-3,4-dihydroxy-5-nitrobenzamide hydrobromide of m.p.205°-207° (from ethanol).

EXAMPLE 28

aa) A solution of 4.93 g of 5-nitrovanillin and 2.7 g of1,2-phenylenediamine in 45 ml of methanol and 15 ml of nitrobenzene isheated to boiling under reflux. After 15 minutes crystals begin toseparate from the red solution. After 18 hours the reaction mixture iscooled to room temperature and diluted with 60 ml of methanol. Thecrystals are filtered under suction and washed with

methanol. There is obtained 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenolof m.p. 198°-200° (from N,N-dimethylformamide/methanol).

In an analogous manner:

ab) From 5-nitrovanillin and 4,5-dichloro-1,2-phenylene-diamine there isobtained 4-(5,6-dichloro-2-benzimidazolyl)-2-methoxy-6-nitrophenol ofm.p. 258°-260° (from N,N-dimethylformamide/ether).

b) A suspension of 860.1 mg of4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol in 10 ml of glacial aceticacid and 10 ml of 48 percent hydrobromic acid is heated to boiling underreflux for 72 hours. The mixture is then evaporated and the residue istreated four times with 50 ml of toluene each time, which is againdistilled each time. There is obtained5-(2-benzimidazolyl)-3-nitropyrocatechol of m.p. >300° (fromacetone/water).

In an analogous manner:

c) From 4-(5,6-dichloro-2-benzimidazolyl)-2-methoxy-6-nitrophenol thereis obtained 5-(5,6-dichloro-2-benzimidazolyl)-3-nitropyrocatechol ofm.p. 282°-284° (from acetone/water).

EXAMPLE 30

A suspension of 29.0 g of2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 700 ml of drymethylene chloride is treated at -20° within 30 minutes with a solutionof 125.3 g of boron tribromide in 300 ml of dry methylene chloride.After the addition the mixture is stirred at -20° for a further 1 hourand at room temperature for 16 hours, then evaporated, the residue istreated cautiously with water while cooling with ice and stirred at 50°for 30 minutes. After cooling the mixture is extracted with ether, theethereal phase is washed with water, dried over sodium sulfate, filteredand evaporated. There is obtained2-bromo-3',4'-dihydroxy-5'-nitroacetophenone of m.p. 138°-140° (frommethylene chloride).

EXAMPLE 31

a) A solution of 3.6 g of ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate in30 ml of acetic anhydride is heated at 110° for 30 minutes in thepresence of a catalytic amount of conc. sulfuric acid, cooled to roomtemperature, the reaction mixture is poured into 150 ml of water andstirred for 60 minutes. The mixture is extracted with ether, washed withsaturated sodium chloride solution, the combined organic extracts aredried sodium sulfate, filtered and evaporated. There is obtained ethyl3,4-diacetoxy-5-nitrophenylglyoxylate of m.p. 87°-89° (fromether/petroleum ether).

In an analogous manner:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one there isobtained 3-(3,4-diacetoxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one of m.p.186°-188° (from methylene chloride/methanol),

c) from 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone there isobtained 3-(3,4-diacetoxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p.241°-243° from methylene chloride/methanol),

d) from 3,4-dihydroxy-5-nitrobenzophenone there is obtained3,4-diacetoxy-5-nitrobenzophenone of m.p. 141°-143° (from methylenechloride/ether),

e) from 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone there is obtained3,4-diacetoxy-2'-fluoro-5-nitrobenzophenone of m.p. 122°-124° (fromether) and

f) from 3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketone there is obtained3,4-diacetoxy-5-nitrophenyl 4-pyridyl ketone of m.p. 148°-150° (frommethylene chloride/ether).

EXAMPLE 32

a) A solution of 2.0 g of 3,5-dinitropyrocatechol in 25 ml of propionicanhydride is heated at 110° for 18 hours in the presence of a catalyticamount of conc. sulfuric acid, the excess anhydride is distilled off at70° in a high vacuum (1.33 Pa), the residue is dissolved in methylenechloride, washed with water, dried over sodium sulfate, filtered andevaporated. There is obtained 1,2-dipropionyloxy-3,5-dinitrobenzene ofm.p. 74°-76° (from methylene chloride/petroleum ether).

In an analogous manner:

b) From3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazine-2-one thereis obtained3-(3,4-dipropionyloxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin-2-one ofm.p. 158°-160° (from methylene chloride),

c) from 6-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-onethere is obtained5-(6-chloro-2-oxo-2H-1,4-benzoxazin-3-yl)-3-nitro-o-phenylene-dipropionateof m.p. 148°-150° (from methylene chloride/ether),

d) from 3-(3,4-dihydroxy-5-nitrophenyl)-7-nitro-2H-1,4-benzoxazin-2-onethere is obtained3-nitro-5-(7-nitro-2-oxo-2H-1,4-benzoxazin-3-yl)-o-phenylene-dipropionateof m.p. 177°-179° (from methanol),

e) from3-(3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-1,4-benzoxazine-6-carboxylicacid there is obtained3-[3,4-bis(propionyloxy)-5-nitrophenyl]-2-oxo-2H-1,4-benzoxazine-6-carboxylicacid of m.p. 192°-194° (from methylene chloride),

f) from 3-nitro-5-(2-quinoxalinyl)pyrocatechol there is obtained3-nitro-5-(2-quinoxalinyl)-o-phenylene-dipropionate of m.p. 152°-154°(from methylene chloride/ether,

g) from 5-(2-benzimidazolyl)-3-nitropyrocatechol there is obtained5-(2-benzimidazolyl)-3-nitro-o-phenylene-dipropionate of m.p. 179°-181°(from ether),

h) from 6,7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinonethere is obtained5-(6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl)-3-nitro-o-phenylene-dipropionateof m.p. 260°-262° (from methylene chloride),

i) from 5-bromo-2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole there isobtained 5-bromo-2-(3,4-dipropionyloxy-5-nitrobenzoyl)-3-methylindole ofm.p. 196°-198° (from ether) and

j) from6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one thereis obtained3-nitro-5-(2,3,4,5-tetrahydro-5-oxo-3-thioxo-as-triazin-6-yl)-o-phenylene-dipropionateof m.p. 237°-239° (from ether).

EXAMPLE 33

a) A solution of 1.09 g of ethyl 3,4-dihydroxy-5-nitrophenylglyoxylatein 6 ml of isobutyric anhydride is heated at 110° for 17 hours in thepresence of a catalytic amount of conc. sulfuric acid. The reactionmixture is then treated ten times with 10 ml of toluene each time,whereby it is evaporated each time at 80° and 18.7 mbar. The oilyresidue is distilled in a bulb-tube at 175°-180° and 8.0 Pa. There isobtained ethyl 3,4-diisobutyryloxy-5-nitrophenylglyoxylate.

In an analogous manner:

b) From 3,5-dinitropyrocatechol there is obtained1,2-diisobutyryloxy-3,5-dinitrobenzene of m.p. 78°-80° (from ether).

c) from 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin-2-onethere is obtained3-(3,4-diisobutyryl-oxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin-2-oneof m.p. 142°-144° (from ether),

d) from 2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline there is obtained2-(3,4-diisobutyryloxy-5-nitrophenyl)-quinoxaline of m.p. 155°-157°(from ether),

e) from 1-methyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinonethere is obtained1-methyl-3-(3,4-diisobutyryloxy-5-nitrophenyl)-2(1H)-quinoxalinone ofm.p. 138°-140° (from ether).

f) from 5-(imidazo[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitropyrocatecholthere is obtained5-(imidazo[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitro-o-phenylenediisobutyrate of m.p. 169°-171° (from methylene chloride),

g) from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone there is obtained5-(bromoacetyl)-3-nitro-o-phenylene diisobutyrate of m.p. 56°-58° (frommethylene chloride/hexane).

h) from 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide thereis obtained 3-nitro-5-(2-isobutyramido-4-thiazolyl)-o-phenylenediisobutyrate of m.p. 157°-1159° (from methylene chloride/ether),

i) from 5-(2-amino-6H-1,3,4-thiadiazin-5-yl)-3-nitropyrocatecholhydrobromide there is obtained3-nitro-5-(2-isobutyramido-4-isobutyryl-1,3,4-thiadiazin-5-yl)-o-phenylenediisobutyrate of m.p. 177°-179° (from ether),

j) from 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-1,4-benzoxazin-2-onethere is obtained3-nitro-5-(2-oxo-6-propyl-2H-1,4-benzoxazin-3-yl)-o-phenylenediisobutyrate of m.p. 131°-133° (from methanol),

k) from 5-(imidazo[1,2-a]pyridin-3-yl)-3-nitropyro-catechol there isobtained 5-(imidazo[1,2-a]pyridin-3-yl)-3-nitro-o-phenylenediisobutyrate of m.p. 137°-139° (from ether),

l) from 5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitropyro-catechol thereis obtained 5-(imidazo[2,1-b]benzothiazol2-yl)-3-nitro-o-phenylenediisobutyrate of m.p. 197°-199° (from methylene chloride/ether and

m) from 3,4-dihydroxy-5-nitrophenyl 2-pyridyl ketone hydrobromide thereis obtained 3-nitro-5-(2-pyridylcarbonyl)-o-phenylene diisobutyrate ofm.p. 83°-85° (from ether/hexane).

EXAMPLE 34

a) A solution of 613.0 mg of ethyl3,4-dihydroxy-5-nitro-phenylglyoxylate in 4 ml of pivaloyl anhydride isheated to 100° for 17 hours in the presence of a catalytic amount ofconc. sulfuric acid, the cooled solution is diluted with ether, washedwith saturated sodium solution, dried over sodium sulfate, filtered andevaporated. The residue is treated ten times with 10 ml of toluene,whereby it is evaporated again each time. After bulb-tube distillation(air-bath) at 175°-180° and 4.0 Pa there is obtained ethyl3,4-dipivaloxyloxy-5-nitrophenylglyoxylate.

In an analogous manner:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin-2-onethere is obtained3-(3,4-dipivaloyloxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin-2-one ofm.p. 180°-192° (from ether),

c) from 3,4-dihydroxy-5-nitrobenzophenone there is obtained3,4-dipivaloyloxy-5-nitrobenzophenone of m.p. 101°-103° (from t-butylmethyl ether) and

d) from 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone there is obtained3,4-dipivaloyloxy-2'-fluorobenzophenone of m.p. 74°-76° (fromlow-boiling petroleum ether).

EXAMPLE 35

A solution of 1.7 g of3-(3,4-dihydroxy-5-nitro-phenyl)-2(1H)-quinoxalinone in 17 ml ofoenanthic anhydride is heated to 110° for 17 hours in the presence of acatalytic amount of conc. sulfuric acid, the excess anhydride is thendistilled in a high vacuum, the residue is dissolved in methylenechloride, the organic solution is washed with water, dried over sodiumsulfate, filtered and evaporated. There is obtained5-(1,2-dihydro-2-oxo-3-quinoxalinyl)-3-nitro-o-phenylene diheptanoate ofm.p. 186°-18820 (from methylene chloride/ether).

EXAMPLE 36

a) 1.26 g of sodium acetate are added to a solution of 1.35 g of2-bromo-3',4'-dihydroxy-5'-nitroacetophenone in 25 ml of alcohol andheated to boiling under reflux. After 6 hours, the reaction mixture isfiltered from separated sodium bromide and evaporated. The residue isdissolved in ethyl acetate. The solution is washed with saturated sodiumchloride solution, dried over sodium sulfate, filtered and evaporated at50°. There is obtained (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate ofm.p. 166°-168° (from ethyl acetate/ether).

In an analogous manner:

b) from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and sodiumisobutyrate there is obtained (3,4-dihydroxy-5-nitrobenzoyl)methylisobutyrate of m.p. 120°-122° (from ethyl acetate/ether) and

c) from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and sodium3,4-dihydroxy-5-nitrophenylglyoxylate there is obtained3,4-dihydroxy-5-nitrophenacyl (3,4-dihydroxy-5-nitrobenzoyl)formate ofm.p. 224°-226° (from methanol/ethyl acetate).

EXAMPLE 37

A suspension of 2.91 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenoneis treated with 1.31 g of thionicotinamide in 50 ml of alcohol andheated to boiling under reflux for 2 hours. After cooling to roomtemperature the crystals are filtered under suction and recrystallizedfrom N,N-dimethylformamide/alcohol. There is obtained3-nitro-5-[2-(3-pyridyl)-4-thiazolyl]pyrocatechol of m.p. 279°-281°.

EXAMPLE 38

A solution of 5.52 g of 2-bromo-3',4'-dihydroxy-5-nitroacetophenone and2.7 g of 2-aminoacetophenone in 100 ml of dry N,N-dimethylformamide isstirred at 90° for 24 hours. The reaction mixture is evaporated, theresidue is dissolved in ethyl acetate, washed with water, dried oversodium sulfate, filtered and evaporated. There is obtained2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole of m.p. 212°-214° (fromn-butanol).

EXAMPLE 39

A suspension of 7.32 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenoneis treated with 4.06 g of 1-(3-pyridinyl)-2-thiourea in 100 ml ofn-butanol and heated to boiling under reflux for 3 hours. After coolingto room temperature the crystals are filtered under suction andrecrystallized from n-butanol. There is obtained3-nitro-5-[2-(3-pyridylamino)-4-thiazolyl]pyrocatechol hydrobromide ofm.p. >300°.

EXAMPLE 40

A suspension of 6.35 g of 2-bromo-3',440 -dihydroxy-5'-nitroacetophenoneis treated with 4.68 g of 1-(3-quinolinyl)-2-thiourea in 150 ml ofn-butanol and heated to boiling under reflux for 3 hours. After coolingto room temperature the crystals are filtered under suction andrecrystallized from n-butanol. There is obtained3-nitro-5-[2-(3-quinolinylamino)-4-thiazolyl]pyrocatechol hydrobromideof m.p. >300°.

EXAMPLE 41

A suspension of 8.28 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenoneis treated with 6.37 g of rac-1-(2-exobornyl)-2-thiourea in 100 ml ofn-butanol and heated to boiling under reflux for 3 hours. After coolingto room temperature the crystals are filtered under suction andrecrystallized from n-butanol. There is obtainedrac-3-nitro-5-[2-(2-exo-bornylamino)-4-thiazolyl]-pyrocatecholhydrobromide of m.p. 262°-264°.

EXAMPLE 42

0.875 ml of pyrrolidine in 35 ml of tetrahydrofuran is treated at 5°with 0.605 ml of acetic acid and subsequently with 1.73 g of3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of6-oxo-4'-(trifluoromethyl)-heptananilide and stirred at 23° under argonfor 56 hours. The residue obtained after evaporating the reactionmixture is partitioned between ethyl acetate and 1N sodium hydroxidesolution. The combined sodium hydroxide extracts are made acid withconc, hydrochloric acid, extracted with ethyl acetate, the combinedethyl acetate extracts are washed with saturated sodium chloridesolution, dried over sodium sulfate, evaporated and the residue ischromatographed on 120 g of silica gel with methylene chloride/methanol(91:9). After recrystallization from ethyl acetate/petroleum ether thereis obtained(E)-8-(3,4-dihydroxy-5-nitrophenyl)-6-oxo-4'-(trifluoromethyl)-7-octenanilide of m.p. 194°-197°.

EXAMPLE 43

a) 26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde are dissolved in 400 mlof acetic anhydride and 5 ml of pyridine. The solution is stirred at 80°for 8 hours, subsequently evaporated, the residue is partitioned betweenice-water and methylene chloride, the organic phase is dried over sodiumsulfate, evaporated and the residue is recrystallized from methylenechloride/petroleum ether. There is obtained2-chloro-3-formyl-6-methoxyphenyl acetate of m.p. 48°-50°.

b) 38 g of 2-chloro-3-formyl-6-methoxyphenyl acetate are introducedportionwise at -5° to -10° within 15 minutes into 150 ml of 98 percentnitric acid. After stirring at -5° for 30 minutes the reaction mixtureis poured into 1.5 1 of ice-water and extracted three times with 500 mlof methylene chloride. The combined organic phases are washed withice-water, dried over sodium sulfate and evaporated. The residue iscrystallized from ether. There is obtained2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate of m.p. 84°-85°.

c) 35.8 g Of 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate aredissolved in 300 ml of methanol. After adding 145 ml of 1N sodiumhydroxide solution the mixture is stirred at 23° for 1 hour. Afterevaporation of the methanol, the residue is diluted with ice-water, madeacid with 2N hydrochloric acid and extracted twice with 400 ml of ethylacetate each time. The organic phases are washed with saturated sodiumchloride solution, dried over sodium sulfate and evaporated. The residueis recrystallized from methylene chloride/petroleum ether. There isobtained 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde of m.p. 130°.

d) 1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde are dissolved in80 ml of methylene chloride, treated with 0.82 ml of boron tribromide,stirred at 23° for 18 hours, the reaction mixture is treated with 5 mlof methanol while cooling with ice, evaporated, the residue is dried ina high vacuum, digested in water, filtered and recrystallized fromacetonitrile. There is obtained2-chloro-3,4-dihydroxy-5-nitrobenzaldehyde of m.p. 193°-195°.

EXAMPLE 44

a) A mixture of 30 g of 2-chloro-3-hydroxy-p-anisaldehyde and 230 ml ofethanol is stirred at 70° for 4 hours in the presence of 12.3 g ofhydroxylamine hydrochloride, the reaction mixture is subsequentlyevaporated the residue is dried in a high vacuum and recrystallized frommethanol/water. There is obtained 2-chloro-3-hydroxy-p-anisaldehydeoxime of m.p. 174°-176°.

b) 21 g of 2-chloro-3-hydroxy-p-anisaldehyde oxime are heated underreflux for 20 hours together with 400 ml of acetic anhydride. Thereupon,the reaction mixture is evaporated, the residue is treated with 300 mlof ice-water, stirred for 1 hour, decanted, the thus-cooled residue ispartitioned between methylene chloride and water, the organic phase isdried over sodium sulfate, evaporated, the residue is dried in a highvacuum, chromatographed on 200 g of silica gel with methylene chlorideand recrystallized from methylene chloride/petroleum ether. There isobtained 2-chloro-3-cyano-6-methoxyphenyl acetate of m.p. 97°-99°.

c) In analogy to Examples 43b and 43c, from2-chloro-3-cyano-6-methoxyphenyl acetate there is obtained2-chloro-3-hydroxy-5-nitro-p-anisonitrile of m.p. 157°-159° (methylenechloride/hexane).

d) In analogy to Example 43d, from2-chloro-3-hydroxy-5-nitro-p-anisonitrile there is obtained2-chloro-3,4-dihydroxy-5-nitro-benzonitrile of m.p. 180° (acetonitrile).

EXAMPLE 45

a) 5.5 g of α-chloro-2-fluoro-3,4-dimethoxytoluene and 4.05 g ofpotassium acetate are stirred at 80° for 25 hours in 50 ml ofdimethylformamide. The reaction mixture is subsequently poured into 150ml of ice-water and extracted with ether. The ether phases are washedwith sodium chloride solution, dried over sodium sulfate and evaporated.2-fluoro-3,4-dimethoxybenzyl acetate is obtained as an oil.

b) 5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate are heated to 80° for1.5 hours together with 50 ml of methanol and 50 ml of 1N sodiumhydroxide solution. After evaporation of the methanol the residue isextracted with methylene chloride. The combined extracts are washed withwater, dried over sodium sulfate and evaporated. The residue ischromatographed on 80 g of silica gel with methylene chloride/methanol(95:5). 2-fluoro-3,4-dimethoxybenzyl alcohol is obtained as an oil.

c) 3.0 g of 2-fluoro-3,4-dimethoxybenzyl alcohol and 5.0 g of manganesedioxide are heated under reflux for 1 hour together with 50 ml ofbenzene. The insoluble constituents are subsequently filtered whilewashing with methylene chloride. The filtrate is evaporated and theresidue is recrystallized from methylene chloride/hexane. There isobtained 2-fluoro-3,4-dimethoxybenzaldehyde of m.p. 52°-54°.

d) 4.4 g of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g ofhydroxylamine hydrochloride are heated under reflux for 5 hours togetherwith 30 ml of ethanol. The reaction mixture is subsequently evaporatedand the residue, dried in a high vacuum at 23°, is introduced into 40 mlof phosphorus oxychloride. After stirring at 23° for 2.5 hours thereaction mixture is evaporated, the residue is treated with ice-water,the precipitate which thereby forms is filtered off, washed with water,taken up in methylene chloride, the methylene chloride solution is driedover sodium sulfate and evaporated. By recrystallization of the residuefrom methylene chloride/hexane there is obtained2-fluoro-3,4-dimethoxybenzonitrile of m.p. 64°-65°.

e) 2.0 g of 2-fluoro-3,4-dimethoxybenzonitrile are dissolved in 60 ml ofmethylene chloride, treated with 1.1 ml of boron tribromide, stirred at23° for 1 hour, subsequently treated with an additional 1.0 ml of borontribromide and stirred at 23° for an additional 80 minutes. Thereupon,the reaction mixture is poured into 100 ml of ice-cold saturated sodiumhydrogen carbonate solution, whereupon the mixture is extracted twicewith 300 ml of ether, the combined ether phases are washed twice withsodium chloride solution, dried over sodium sulfate, evaporated and theresidue is chromatographed on 50 g of silica gel with methylene chlorideand methylene chloride/methanol (97:3). There is obtained2-fluoro-3-hydroxy-p-anisonitrile of m.p. 198°-200°.

f) 0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile are dissolved in 10 ml ofacetic anhydride and 0.5 ml of pyridine, whereupon the mixture isstirred at 120° for 2 hours. The reaction mixture is subsequentlyevaporated and the residue is partitioned between ice-water andmethylene chloride. The organic phase is dried over sodium sulfate andevaporated, and the residue is recrystallized from methylenechloride/hexane. There is obtained 3-cyano-2-fluoro-6-methoxyphenylacetate of m.p. 90°-91°.

g) 0.8 g of 3-cyano-2-fluoro-6-methoxyphenyl acetate are introduced inthree portions at -15° into 5 ml of 96 percent nitric acid, whereuponthe mixture is stirred at -10° for 1 hour. Thereupon, the reactionmixture is poured on to 50 g of ice. The mixture is extracted twice with70 ml of ethyl acetate each time. The combined organic phases are washedwith saturated sodium chloride solution, dried over sodium sulfate andevaporated. The thus-obtained residue is dissolved in 50 ml of 1N sodiumcarbonate solution and 50 ml of methanol, whereupon the solution isstirred at 23° for 1 hour and the methanol is distilled off. The residalaqueous phase is adjusted to pH 2 at 0° with conc. hydrochloric acid andextracted twice with 100 ml of ethyl acetate. The combined organicphases are washed with saturated sodium chloride solution, dried oversodium sulfate and evaporated, and the residue is chromatographed on 45g of silica gel with methylene chloride/methanol (97:3). Afterrecrystallization from ether/hexane there is obtained2-fluoro-3-hydroxy-5-nitro-p-anisonitrile of m.p. 112°-113°.

h) 550 mg of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile are dissolved in30 ml of methylene chloride, whereupon the solution is treated with 0.44ml of boron tribromide. After stirring at 23^(e) for 6 hours anadditional 0.1 ml of boron tribromide are added thereto, whereupon themixture is stirred at 23° for an additional 1.5 hours. Thereupon, 3 mlof ethanol are added thereto at -15°. The reaction mixture is evaporatedand the residue is dried in a high vacuum at 23°. By recrystallizationfrom ether/hexane there is obtained2-fluoro-3o4-dihydroxy-5-nitrobenzonitrile of m.p. 154°.

EXAMPLE 46

a) 9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid are suspended in 95 ml ofthionyl chloride. The suspension is stirred at 80° for 1 hour. Bytwo-fold evaporation with the addition of absolute toluene there areobtained 10 g of 3,4-dimethoxy-5-nitrobenzoyl chloride which isdissolved in 100 ml of tetrahydrofuran. This solution is added dropwiseto 300 ml of 28 percent aqueous ammonia. The mixture is subsequentlystirred at 40° for 2 hours and cooled to 5°. The crystalline precipitateis filtered off. There is obtained 3,4-dimethoxy-5-nitrobenzamide ofm.p. 182°-185°.

b) 2.46 g of chlorine are introduced while cooling with ice into amixture of 8.0 g of sodium hydroxide, 50 ml of water and 30 g of ice.Thereupon, 6.5 g of 3,4-dimethoxy-5-nirobenzamide suspended in 5 ml oftetrahydrofuran are slowly added thereto. The reaction mixture is heatedto 70° within 30 minutes, stirred at 70° for 1 hour, cooled to 5° andthe separated crystals are filtered off. There is obtained3,4-dimethoxy-5-nitroaniline of m.p. 129°-131°. By extraction of thefiltrate with ethyl acetate, drying the extract over sodium sulfate,concentration and crystallization of the residue with the addition ofether there can be obtained an additional portion of3,4-dimethoxy-5-nitroaniline.

c) 10 g of finely powdered 3,4-dimethoxy-5-nitroaniline are suspended in15 ml of 12N hydrochloric acid and 40 ml of water, whereupon thesuspension is stirring at 30° for 1 hour. Thereupon, 3.8 g of sodiumnitrite dissolved in 20 ml of water are added dropwise thereto at -5°within 15 minutes. The solution is stirred at -5° for 30 minutes and thecold diazonium salt solution is added dropwise within 45 minutes to 100ml of pyridine of 40°. The mixture is subsequently stirred at 70° for 1hour. The reaction mixture is evaporated and the residue is taken up in300 ml of ethyl acetate. It is extracted three times with 200 ml of 2Nhydrochloric acid each time. The acidic-aqueous phase is adjusted to pH9 with conc. ammonia and extracted with methylene chloride. The combinedmethylene chloride extracts are dried over sodium sulfate andevaporated, and the residue is chromatographed on 250 g of silica gelwith ethyl acetate. After crystallization from methylene chloride/hexanethere is obtained 2-(3,4-dimethoxy-5-nitrophenyl)pyridine of m.p.89°-90°.

d) 1.5 g of 2-(3,4-dimethoxy-5-nitrophenyl)pyridine are dissolved in 30ml of 48 percent aqueous hydrobromic acid. The reaction mixture isstirred at 100° for 16 hours and at 23° for 18 hours. The precipitatewhich thereby forms is filtered and recrystallized from methanol/ether.There is obtained 3-nitro-5-(2-pyridyl)pyrocatechol hydrobromide of m.p.239°-240°.

EXAMPLE 47

a) 2.76 ml of 2-bromopyridine dissolved in 30 ml of absolutetetrahydrofuran are treated -60° within 30 minutes with 19.2 ml of 1.6Mn-butyl lithium solution (in hexane), whereupon the mixture is stirredat -60° for 30 minutes. 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehydedissolved in 50 ml of tetrahydrofuran are then added dropwise thereto at-40° within 30 minutes. The reaction mixture is warmed to 0° within 2hours, poured into ice-water and extracted with ethyl acetate. Thecombined extracts are dried over sodium sulfate and evaporated, and theresidue is chromatographed on 200 g of silica gel with ethyl acetate.There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol asa brown oil.

b) 7 g of manganese dioxide and added portionwise to 4.0 g ofα-(3,4-dimethoxy-5-nitrophenyl)-2-pyridine-methanol dissolved in 100 mlof acetone while constantly heating under reflux over a period of 2.5hours. Thereupon, the mixture is heated under reflux for an additional 2hours. The manganese salts are subsequently filtered and the residueobtained after evaporation is recrystallized from ether/hexane. There isobtained 3,4-dimethoxy-5-nitrophenyl 2-pyridyl ketone of m.p. 113°.

c) 1.5 g of 3,4-dimethoxy-5-nitrophenyl-2-pyridyl ketone dissolved in 30ml of 48 percent hydrobromic acid are stirred at 100° for 18 hours.Thereupon, the reaction mixture is evaporated and the residue isrecrystallized from acetonitrile/methanol. There is obtained3,4-dihydroxy-5-nitrophenyl 2-pyridyl ketone hydrobromide of m.p. 213°.

EXAMPLE 48

a) 11.3 g of tin dichloride dihydrate are added to 2.25 g of3',4'-dimethoxy-5'-nitroacetophenone dissolved in 50 ml of ethanol,whereupon the mixture is stirred at 75° for 30 minutes. Thereupon, thereaction mixture is poured on to 100 g of ice, neutralized with about300 ml of saturated sodium hydrogen carbonate solution and treated with150 ml of methylene chloride. The mixture is filtered and the methylenechloride phase is separated. This is dried over sodium sulfate andevaporated, and the residue is recrystallized from ether/petroleumether. There is obtained 5'-amino-3',4'-dimethoxyacetophenone of m.p.63°-65°.

b) A solution of 5.2 g of sodium nitrite in 20 ml of water is addeddropwise at 0° within 20 minutes to 14.0 g of5'-amino-3',4'-dimethoxyacetophenone dissolved in 155 ml of 1Nhydrochloric acid. After stirring at -2° for 30 minutes the colddiazonium salt solution is added dropwise within 30 minutes at 5°-10° toa solution of 8.7 g of copper(I) cyanide and 5.45 g of potassium cyanidein 60 ml of water. After completion of the addition 200 ml of methylenechloride are added, and the reaction mixture is stirred at 23° for 3hours and then filtered. The organic phase is separated, washed withwater, dried over sodium sulfate and evaporated. The residue isrecrystallized from methylene chloride/petroleum ether. There isobtained 5'-cyano-3',4'-dimethoxyacetophenone of m.p. 125°-126°.

c) 3.75 g Of aluminum powder and 28.5 g of iodine are heated underreflux for 2 hours in 160 ml of absolute benzene. 3.0 g of5'-cyano-3',4'-dimethoxyacetophenone and 0.5 g of tetra-n-butylammoniumiodide are then added at 20, whereupon the mixture is heated underreflux for 1 hour. Thereupon, the mixture is treated at 20° with 50 g ofice and filtered. The residue is washed with ethyl acetate. The phasesare separated and the aqueous phase is extracted twice with ethylacetate. The combined organic phases are washed with 20 percent sodiumthiosulfate solution, dried over sodium sulfate and evaporated. Thethus-obtained residue is dissolved in 20 ml of acetic anhydride and 0.5ml of pyridine and stirred at 120° for 6 hours. The mixture issubsequently evaporated and the residue is partitioned between methylenechloride and ice-water. The methylene chloride phase is dried oversodium sulfate and evaporated, and the residue is chromatographed on 100g of silica gel with methylene chloride. After recrystallization fromether there is obtained 5'-cyano-3',4'-diacetoxyacetophenone of m.p.76°-79°.

EXAMPLE 49

0.33 g of 5'-cyano-3',4'-diacetoxyacetophenone dissolved in 3.3 ml ofmethanol is treated with 2.7 ml of 1.0N sodium hydroxide solution andthe reaction mixture is stirred at 23° for 45 minutes. The mixture issubsequently acidified with 2N hydrochloric acid, diluted with 5 ml ofsaturated sodium chloride solution and extracted twice with 30 ml ofethyl acetate each time. The combined ethyl acetate phases are driedover sodium sulfate and evaporated. The residue is recrystallized fromtoluene/acetonitrile. There is obtained5'-cyano-3',4'-dihydroxyacetophenone as brownish crystals whichdecompose above 215°.

EXAMPLE 50

a) 3.48 g of phenyltrimethylammonium bromide dibromide dissolved in 30ml of tetrahydrofuran are added dropwise at room temperature within 45minutes to 1.9 g of 5'-cyano-3',4'-dimethoxyacetophenone dissolved in 30ml of tetrahydrofuran, whereupon the mixture is stirred for 30 minutes.Thereupon, the reaction mixture is poured into 120 ml of ice-water andextracted three times with 70 ml of methylene chloride. The combinedmethylene chloride phases are washed with 2N sulfuric acid, dried oversodium sulfate and evaporated. The residue is chromatographed on 20 g ofsilica gel with methylene chloride. After recrystallization frommethylene chloride/hexane there is obtained5-(bromoacetyl)-2,3-dimethoxybenzonitrile of m.p. 138°-141°.

b) 1.45 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile and 1.12 g ofselenium dioxide are stirred at 120° for 18 hours in 10 ml of n-hexanol.After cooling to room temperature the mixture is diluted with 20 ml ofmethylene chloride and filtered. The filtrate is washed with water,dried over sodium sulfate and evaporated. The residue is chromatographedon 70 g of silica gel with hexane/ether (2:1). There is obtained hexyl(3-cyano-4,5-dimethoxy-phenyl)glyoxylate as an oil.

c) 4.8 ml of boron tribromide dissolved in 20 ml of methylene chlorideare added dropwise while cooling with ice within 20 minutes to 4.0 g ofhexyl (3-cyano-4,5-dimethoxyphenyl)glyoxylate dissolved in 100 ml ofmethylene chloride and the reaction mixture is stirred at roomtemperature for 18 hours. 40 ml of methanol are subsequently addeddropwise thereto at -60° , the mixture is stirred at room temperaturefor 1 hour and evaporated. The residue is taken up in methanol. It isheated under reflux for 10 minutes, evaporated to dryness and dried in ahigh vacuum. The thus-obtained crude product is recrystallized fromacetonitrile. There is obtained methyl(3-cyano-4,5-dihydroxyphenyl)glyoxylate of m.p. 252°.

EXAMPLE 51

1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl)-glyoxylate and 0.60 g of2-amino-p-cresol are stirred at 120° for 70 minutes in 2 ml ofdimethylformamide. The mixture is subsequently cooled to roomtemperature and diluted with 15 ml of water. The precipitate is filteredand dried in a water-jet vacuum at 80° for 6 hours. Afterrecrystallization from acetonitrile there is obtained2,3-dihydroxy-5-(6-methyl-2-oxo-2H-1,4-benzoxazin-3-yl)-benzonitrile ofm.p. 278°-280°.

EXAMPLE 52

a) A solution of 2.5 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 mlof absolute tetrahydrofuran is treated with 1.1 ml of ethylisocyanoacetate and subsequently with a solution of 3.0 ml oftriethylamine in 10 ml of tetrahydrofuran and stirred at roomtemperature for 48 hours. After distillation of the solvent, the residueis extracted with ethyl acetate/water. The crude product obtained afterevaporation is chromatographed on a 20-fold amount of silica gel withethyl acetate. After recrystallization from ethyl acetate/hexane thereis obtained ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazole-carboxylatein the form of yellow crystals of m.p. 109°-110°.

b) 1.0 g of ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolecarboxylateis treated with 10 ml of constant-boiling hydrobromic acid and stirredat 140° for 2 hours. After distillation of the excess hydrobromic acid,the yellow residue is recrystallized from ethanol/acetone. There isobtained 2-amino-3',4'-dihydroxy-5'-nitroacetophenone hydrobromide inthe form of yellow crystals of m.p. >250° (dec.).

EXAMPLE 53

a) 10 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are suspended in100 ml of ethanol, treated with 1.7 g of methylhydrazine and heatedunder reflux for 16 hours. After distillation of about 50 mi of ethanol,the mixture is cooled to 0° and the separated precipitate is filteredunder suction. After recrystallization from ethanol there is obtained3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol in the form ofyellow crystals of m.p. 200°-202°.

b) 2.0 g of 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyroazol-5-ol aresuspended in 100 ml of methylene chloride. After cooling to -40° asolution of 4.9 ml of boron tribromide in 60 ml of methylene chloride isadded dropwise thereto within 1 hour. The mixture is subsequentlystirred at room temperature for 16 hours, cooled to -20° and treatedwithin 30 minutes with 100 ml of ethanol. After stirring at roomtemperature for 1 hour, the solvent is removed by distillation in awater-jet vacuum at 40° . The residue is treated three times with amixture of 100 ml of ethanol/toluene each time, with the solvent beingdistilled each time. The residue is recrystallized from ethanol. Thereis obtained 5-(5-hydroxy-1-methylpyrazol-3-yl)-3-nitropyrocatecholhydrobromide in the form of yellow crystals of m.p. >250° .

EXAMPLE 54

a) 16.8 g (0.7 g-atom) of magnesium are treated with 15 ml of ethanoland, after adding 2 ml of carbon tetrachloride, the reaction isinitiated by heating. A solution of 130.3 g of tert.butyl ethyl malonatein 70 ml of ethanol and 600 ml of absolute ether is added dropwisethereto while stirring within about 30 minutes so that the reactionproceeds at the reflux temperature. The mixture is subsequently stirredat 50° for an additional 3 hours and the solvent is distilled at 40° ina water-jet vacuum. The residue is dissolved in 900 ml oftetrahydrofuran. To this solution is added dropwise while stirring at50° a solution of 170 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 700ml of absolute tetrahydrofuran and the mixture is stirred at the refluxtemperature for 1 hour. The solvent is distilled at 40° in a water-jetvacuum. The residue is treated with 11 of ether. 260 ml of 3N sulfuricacid are added thereto while cooling and stirring and the mixture isstirred for 30 minutes. The aqueous phase is extracted twice with 600 mlof ether each time. The organic phase is washed neutral with water,dried over sodium sulfate and evaporated. The brown oil obtained isfiltered over 1 kg of silica gel with toluene. The resulting mixture,consisting of ethyl tert.butyl (3,4-dimethoxy-5-nitrobenzoyl)malonateand ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate, is dissolved in 600 mlof methylene chloride and treated while stirring within about 30 minuteswith 193 ml of trifluoroacetic acid. The mixture is subsequently stirredat 40° for 2 hours and then evaporated at 40° in a water-jet vacuum. Theoil obtained is extracted with ether/water. The organic phase is driedover sodium sulfate and evaporated. After dissolution in diisopropylether/hexane and cooling the separated crystals are filtered undersuction and recrystallized from diisopropyl ether. There is obtainedethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate in the form of slightlyyellowish crystals of m.p. 67° -68°.

b) 10.0 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are reactedwith 4.0 g of phenylhydrazine in analogy to Example 53a. Afterrecrystallization from methylene chloride/ethanol, there is obtained3-(3,4-dimethoxy-5-nitrophenyl)-l-phenyl-2-pyrazolin-5-one in the formof yellow crystals of m.p. 190°-192°.

c) In analogy to Example 53b, with boron tribromide there is obtainedtherefrom 5-(5-hydroxy-l-phenylpyrazol-3-yl)-3-nitropyrocatecholhydrobromide in the form of yellow crystals of m.p. >220° (dec.).

EXAMPLE 55

20.1 g of diethyl (3,4-dimethoxy-5-nitrobenzoyl)-malonate are dissolvedin 200 ml of methylene chloride, whereupon the solution is cooled to-20° and at this temperature there is added dropwise while stirringwithin 15 minutes a solution of 68.1 g of boron tribromide in 120 ml ofmethylene chloride. The mixture is subsequently stirred at roomtemperature overnight. After cooling to -20° , the mixture is treatedwith 300 ml of ethanol and stirred at room temperature for 30 minutes.The solvent is distilled in a water-jet vacuum at 40° . The residue istreated with 300 ml of ice-water and methylene chloride. The organicphase is washed with water, dried over sodium sulfate and evaporated.The crude product obtained is chromatographed on a 10-fold amount ofsilica gel with toluene. After crystallization from methylenechloride/hexane there is obtained ethyl(3,4-dihydroxy-5-nitrobenzoyl)acetate in the form of yellow crystals ofm.p. 136°-137°.

EXAMPLE 56

2.0 g of ethyl (3,4-dihydroxy-5-nitrobenzoyl)acetate are suspended in 50ml of ethanol. After treatment with 0.4 g of hydrazine hydrate themixture is held at the reflux temperature for 16 hours. Afterdistillation of the solvent, the residue is held at the boilingtemperature for 5 minutes with 50 ml of ethyl acetate. The separatedprecipitate is filtered under suction and the filtrate is concentratedto 10 ml. The crystals, which separate in the cold, are filtered undersuction. There is obtained 5-(5-hydroxypyrazol-3-yl)-3-nitropyrocatecholin form of orange crystals of m.p. 228° (dec.).

EXAMPLE 57

7.3 g of 3,4-dihydroxy-5-nitrobenzoic acid are treated with 30 ml ofacetic anhydride, whereupon the mixture is held at the refluxtemperature for 8 hours. The reaction mixture is poured on to ice. Theseparated precipitate is filtered under suction, washed with water andtaken up in methylene chloride. The organic phase is dried over sodiumsulfate and evaporated. The residue obtained is recrystallized frommethylene chloride/n-hexane in the cold. There is obtained3,4-diacetoxy-5-nitrobenzoic acid in the form of colorless crystals ofm.p. 126°-127°.

EXAMPLE 58

a) 9.7 g of 3,4-diacetoxy-5-nitrobenzoic acid are treated with 12.5 mlof thionyl chloride, whereupon the mixture is stirred at 100° for 1.5hours. After distillation of the excess thionyl chloride, the5-(chlorocarbonyl)-2-nitro-o-phenylene diacetate is distilled, b.p. 160°(26.7 Pa).

b) 3.2 g of 5-(chlorocarbonyl)-2-nitro-o-phenylene diacetate aredissolved in 50 ml of dimethylformamide. The ice-cold solution istreated while stirring with a solution of 2.2 ml of diethylamine in 20ml of dimethylformamide. The mixture is subsequently stirred at roomtemperature for 1 hour, whereupon the solvent is

distilled in a water-jet vacuum at 50°. The residue obtained is treatedwith water and methylene chloride. The organic phase is dried oversodium sulfate and evaporated. The yellow resin obtained is crystallizedfrom methylene chloride/ether. There is obtainedN,N-diethyl-3,4-dihydroxy-5-nitrobenzamide in the form of yellowcrystals of m.p. 145°-146°.

EXAMPLE 59

3.3 g of 5-(chlorocarbonyl)-3-nitro-o-phenylenediacetate are dissolvedin 50 ml of dimethyl-formamide, whereupon the solution is treated at0°-5 while stirring and within 40 minutes with a solution of 3.02 ml of2,2-diethylaminoethylamine in 20 ml of dimethyl-formamide. The mixtureis subsequently stirred at room temperature for 30 minutes. The solventis distilled in a water-jet vacuum at 60°. The residue is extractedtwice with 20 ml of ethanol each time, dissolved in hot ethanol andtreated with an excess of ethanolic hydrochloric acid, whereupon themixture is evaporated. After recrystallization from ethanol/ethylacetate there is obtainedN-[2-(diethylamino)ethyl]-3,4-dihydroxy-5-nitrobenzamide hydrochloridein the form of yellow crystals of m.p. 139° (dec.).

EXAMPLE 60

a) 10.0 g of 2,3-dimethoxy-5-nitrobenzaldehyde are treated with 50 ml ofglacial acetic acid and 50 ml of constant-boiling hydrobromic acid andheld at the reflux temperature for 7 hours. After treatment with ice theseparated precipitate is filtered under suction, washed with water andtaken up in ethyl acetate. The organic phase is dried over sodiumsulfate and evaporated. The crude product obtained is filtered oversilica gel with ethyl acetate. After crystallization from ethylacetate/hexane there is obtained 2,3-dihydroxy-5-nitro-benzaldehyde inthe form of brownish crystals of m.p. 226°-228°.

b) 4.5 g of 2.3-dihydroxy-5-nitrobenzaldehyde are suspended in 75 ml ofwater. After treatment with 4.2 g of hydroxylamine o-sulphonic acid, themixture is stirred at 65° for 16 hours. After cooling the separatedcrystals are filtered under suction and washed with water. The filtrateis extracted with ethyl acetate. The crystals and the dried organicphase are combined, whereupon the mixture is evaporated and the residueis recrystallized from diisopropyl ether. There is obtained2,.3-dihydroxy-5-nitrobenzonitrile in the form of yellow crystals ofm.p. 186°-188°.

EXAMPLE 61

a) 4.0 g of 3,4-dimethoxy-5-nitro-benzonitrile are dissolved in 50 ml ofdimethylformamide, whereupon the solution is treated with 1.66 g ofammonium chloride and 2.02 g of sodium azide and stirred at 125° for 31hours. After in each case 8 and 15 hours the same amounts of ammoniumchloride and sodium azide are added thereto. After cooling the mixtureis poured on to ice. The separated precipitate is filtered undersuction, washed with water and dried. There is obtained2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol in the form of orangecrystals of m.p. >240° (dec.).

b) 4.0 g of 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol are treatedwith 40 ml of constant-boiling hydrobromic acid, whereupon the mixtureis stirred at 140° for 8 hours under a nitrogen atmostphere. Aftercooling, the mixture is poured on to ice. The separated precipitate isfiltered under suction and recrystallized from ether. There is obtained3-nitro-5-(1H-tetrazol-5-yl)-pyrocatechol in the form of orange crystalsof m.p. >240° (dec.).

EXAMPLE 62

A total of 7.2 g of 3,4-dihydroxy-5-nitro-benzonitrile are introducedportionwise into 130 ml of conc. sulfuric acid while stirring within 10minutes, whereupon the mixture is stirred at 50° for 4 hours. Thereaction mixture is poured into 800 ml of ice-water. The separatedprecipitate is filtered under suction, washed with water and taken up inethyl acetate. The organic phase is dried over sodium sulfate andevaporated. After recrystallization from acetone/ethyl acetate there isobtained 3,4-dihydroxy-5-nitrobenzamide in the form of orange crystalsof m.p. 235°-236°.

EXAMPLE 63

a) A solution of 11.25 g of 2-hydroxyacetophenone in 100 ml of absolutedimethylformamide is added dropwise under an argon atmosphere within 15minutes to a suspension of 3.6 g of a 55 percent sodium hydridedispersion in 50 ml of absolute dimethylformamide and the mixture isstirred at room temperature for 1 hour. After cooling to 0°, a solutionof 20.3 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of absolutedimethylformamide is added dropwise thereto within 20 minutes and themixture is stirred at room temperature overnight. The reaction mixtureis poured into ice-water, whereupon the mixture is extracted twice with250 ml of ethyl acetate each time. The organic phase is extracted twicewith 100 ml of sodium chloride solution each time, dried over sodiumsulfate and evaporated. The brown oil obtained is heated in 100 ml oftoluene. The separated precipitate is filtered under suction and thefiltrate is chromatographed on a 30-fold amount of silica gel withtoluene/ethyl acetate (4:1). After recrystallization from ethylacetate/hexane there is obtained o-acetylphenyl3,4-dimethoxy-5-nitrobenzoate in the form of yellowish crystals of m.p.108°-109°.

b) 10.0 g of o-acetylphenyl 3,4-dimethoxy-5-nitrobenzoate are dissolvedin 50 ml of pyridine. After treatment with 8.12 g of powdered and driedpotassum hydroxide, the mixture is stirred at 80° for 5 minutes. Aftercooling the mixture is poured on to ice. The aqueous solution is madeacid by treatment with 3N hydrochloric acid. The separated precipitateis removed by filtration under suction. After recrystallization fromethyl acetate/hexane, there is obtained1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione inthe form of yellowish crystals of m.p. 188°-189°.

c) A solution of 1.82 g of boron tribromide in 20 ml of methylenechloride is added dropwise within about 20 minutes to a solution of 500mg of1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione in50 ml of methylene chloride while stirring and under an argon atmosphereat -20°, whereupon the mixture is stirred at room temperature overnight.After cooling to -20° the mixture is treated dropwise with 25 ml ofethanol and evaporated at 40° in a water-jet vacuum. Afterrecrystallization from ethanol, there is obtained1-(3,4-dihydroxy-5-nitrophenyl)-3-(o-hydroxyphenyl)-1,3-propanedione inthe form of yellow crystals of m.p. 251°-252°.

EXAMPLE 64

a) A solution of 2.0 g of o-acetylphenyl 3,4-dimethoxy-5-nitrobenzoatein 12.5 ml of glacial acetic acid is treated with 0.94 g of sodiumacetate and held at the reflux temperature for 4 hours. After coolingthe mixture is poured into ice-water. The separated crystals arefiltered under suction. After recrystallization from ethylacetate/hexane there is obtained2-(3,4-dimethoxy-5-nitrophenyl)-4H-1-benzopyran-4-one in the form ofcolorless crystals of m.p. 216°-217°.

b) A solution of 10 ml of boron tribromide in 50 ml of methylenechloride are added dropwise within 30 minutes at -10° to a solution of1.0 g of 2-(3,4-dimethoxy-5-nitrophenyl)-4H-1-benzopyran-4-one in 100 mlof methylene chloride under an argon atmosphere, whereupon the mixtureis stirred at room temperature overnight. After cooling to -20°, 20 mlof ethanol are added dropwise thereto. The mixture is then evaporated ina water-jet vacuum. The yellow residue obtained is extracted withwater/ethyl acetate. The organic phase is washed with water, dried oversodium sulfate and evaporated. After recrystallization fromethanol/ethyl acetate, there is obtained2-(3,4-dihydroxy-5-nitrophenyl)-4H-1-benzopyran-4-one in the form ofyellow crystals of m.p. >240° (dec.).

EXAMPLE 65

a) 92 ml of n-butyl lithium solution (1.6M in hexane) are added dropwiseat -70° within 20 minutes to 33.0 g of 4-bromobenzotrifluoride(dissolved in 150 ml of tetrahydrofuran). After stirring at -70° for 45minutes, 36 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 mlof tetrahydrofuran) are added dropwise thereto at between -70° and -60°.The reaction mixture is stirred at -70° for 2 hours and at 0° for 1hour, poured into a mixture of ice and 100 ml of 2N sulfuric acid andextracted twice with 500 ml of ether. The combined ether phases arewashed with saturated sodium chloride solution, dried over sodiumsulfate and evaporated. There is obtained4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol which can be useddirectly in the subsequent reaction step.

b) 52.6 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol(dissolved in 500 ml of methylene chloride) are treated within 10minutes at 20° with 30.6 g of pyridinium chlorochromate and stirred at20° for 2 hours. The precipitate formed is subsequently filtered andwashed with methylene chloride. The filtrate is evaporated and theresidue is chromatographed on 150 g of silica gel with methylenechloride. After recrystallization from methylene chloride/hexane, thereis obtained 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone ofmelting point 101°.

c) 70 ml. of 33 percent hydrobromic acid in acetic acid are added within15 minutes at 10° to 20 g of4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in150 ml of methylene chloride). After stirring at 20° for 1.5 hours, thereaction mixture is poured into 600 ml. of ice-water: the methylenechloride phase is separated and the aqueous phase is extracted twicemore with 100 ml. of methylene chloride. The combined methylene chloridephases are washed with 600 ml of water, dried over sodium sulfate andevaporated. The residue is chromatographed on 150 g of silica gel withmethylene chloride. After recrystallization from methylenechloride/hexane, there is obtained4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone of melting point97°.

d) 3.2 ml of 65 percent nitric acid are added dropwise within 10 minutesat 20° to 12.8 g of 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone(dissolved in 160 ml of acetic acid). After stirring for 1.5 hours, thereaction mixture is poured into 600 ml of ice-water and the precipitateformed is filtered off, washed with water and dissolved in methylenechloride. The methylene chloride solution is dried over sodium sulfateand evaporated, and the residue is recrystallized from methylenechloride/hexane. There is obtained4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone of meltingpoint 172°.

e) 2.0 g of 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone(dissolved in 20 ml of 33 percent hydrobromic acid in glacial aceticacid) are stirred at 90° for 18 hours. Thereupon. 20 ml of 48 percentaqueous hydrobromic acid are added thereto, whereupon the mixture isstirred at 110° for an additional 18 hours. The reaction mixture issubsequently evaporated under reduced pressure and the residue isrecrystallized from water. There is obtained3,4-dihydroxy-5-nitro-4'-(trifluoromethyl)benzophenone of melting point116°-118°.

EXAMPLE 66

a) 18.7 g of4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolvedin 250 ml of tetrahydrofuran) are treated at room temperature with 27.5ml of 2N potassium hydroxide solution, whereupon the mixture isevaporated. The residue is treated with 200 ml of toluene, whereupon themixture is again evaporated. Thereupon, the mixture is heated with 400ml of toluene for 4 hours with the separation of water and under reflux.100 ml of toluene are distilled and 10 ml of dimethylformamide and 20 mlof dimethyl sulfate (freshly distilled) are added, whereupon the mixtureis heated under reflux for 5 hours. 300 ml of 1N sodium hydroxidesolution are subsequently added at 20°. The reaction mixture is stirredfor 30 minutes and treated with 200 ml of ether. The organic phase isseparated; the aqueous phase is extracted twice more with 100 ml ofether; the combined ether phases are dried over sodium sulfate andevaporated, and the residue is chromatographed on 70 g of silica gelwith methylene chloride. After recrystallization from methylenechloride/hexane there is obtained3,4-dimethoxy-5-nitro-4'-(trifluoromethyl)benzophenone of melting point115°.

b) 49.5 g of tin dichloride dihydrate are added to 16.0 g of3,4-dimethoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolved in 300ml of ethanol), whereupon the mixture is stirred at 75° for 30 minutes.Thereupon, the reaction mixture is poured into 800 ml of ice-water. Itis neutralized with 28 percent sodium hydroxide solution and extractedthree times with 600 ml of methylene chloride. The combined methylenechloride phases are washed with water, dried over sodium sulfate andevaporated. After recrystallization from methylene chloride/hexane thereis obtained 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone ofmelting point 95°-96°.

c) 3.25 g of 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone(dissolved in 50 ml of acetone) are evaporated under reduced pressureafter the addition of 15 ml of 2N sulfuric acid. The thus-obtainedresidue is suspended in 20 ml of acetic acid, diluted with 100 ml ofwater and treated at 5° with a solution of 700 mg of sodium nitrite in10 ml of water. It is stirred at 5° for 1 hour. Thereupon, the diazoniumsalt solution is filtered, added at 5° to a solution of 2.0 g of sodiumcyanide and 1.0 g of copper(I) cyanide in 20 ml of water and stirred at5° for 1 hour. Thereupon, 200 ml of methylene chloride are addedthereto. Insoluble constituents are filtered off. The phases areseparated; the aqueous phase is extracted twice more with 100 ml ofmethylene chloride. The combined methylene chloride phases are washedwith water, dried over sodium sulfate and evaporated. The residue ischromatographed on 30 g of silica gel with methylene chloride. Afterrecrystallization from methylene chloride/hexane, there is obtained5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone of melting point130°.

d) 1.5 g of 5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone(dissolved in 75 ml of methylene chloride) are treated at 5° with 2.18ml of boron tribromide, whereupon the mixture is stirred at roomtemperature for 18 hours. The reaction mixture is subsequently dilutedwith 50 ml of methylene chloride. The mixture is heated under reflux foran additional 4 hours, treated at -70° with 15 ml of methanol, stirredat room temperature for 2 hours, evaporated, the residue is dried invacuo and partitioned between ethyl acetate and ice-water. The aqueousphase is extracted twice more with ethyl acetate. The combined ethylacetate phases are dried over sodium sulfate and evaporated. Thethus-obtained material is stirred at 130° for 6 hours with 10 ml ofacetic anhydride and 1 ml of pyridine. The mixture is evaporated and theresidue is partitioned between ice-water and methylene chloride. Themethylene chloride phase is dried over sodium sulfate and evaporated,and the residue is chromatographed on 30 g of silica gel with methylenechloride. The thus-obtained diacetate is dissolved in 10 ml of methanol.The solution is treated with 4.2 ml of 1N sodium hydroxide solution,stirred at 0° for 1 hour, neutralized with acetic acid, evaporated andpartitioned between ethyl acetate and saturated sodium chloridesolution. The ethyl acetate phases are dried over sodium sulfate andevaporated, and the residue is recrystallized from methylene chloride.There is obtained 5-cyano-3,4-dihydroxy-4'-(trifluoromethyl)benzophenoneof melting point 204°-206°.

In an analogous manner:

a1) From 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone of m.p. 86°-88°(from ether/low-boiling petroleum ether),

b1) from 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone there is obtained5-amino-3,4-dimethoxy-2'-fluorobenzophenone of m.p. 93°-95° (fromether/low-boiling petroleum ether).

c1) from 5-amino-3,4-dimethoxy-2'-fluorobenzophenone there is obtained5-benzoyl-2,3-dimethoxy-2'-fluorobenzonitrile of m.p. 132°-134° (frommethylene chloride/low-boiling petroleum ether) and

d1) from 5-benzoyl-2,3-dimethoxy-2'-fluorobenzonitrile there is obtained5-benzoyl-2,3-dihydroxy-2'-fluorobenzo- nitrile of m.p. 228°-230° (fromether/low-boiling petroleum ether).

In an analogous manner:

b2) from 3,4-dimethoxy-5-nitrobenzophenone there is obtained5-amino-3,4-dimethoxybenzophenone as an amorphous solid,

c2) from 5-amino-3,4-dimethoxybenzophenone there is obtained5-benzoyl-2,3-dimethoxybenzonitrile of m.p. 98°-100° (from ether/hexane)and

d2) from 5-benzoyl-2,3-dimethoxybenzonitrile there is obtained5-benzoyl-2,3-dihydroxybenzonitrile of m.p. 212°-214° (from ethylacetate/ether).

EXAMPLE 67

a) A solution of 16.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80ml of pyridine is added dropwise to a solution of 2.68 g of1-methylimidazole and 6.6 g of triethylamine in 80 ml of pyridine,whereupon the mixture is stirred at 60° for 3 hours. After treatmentwith 1.70 ml of 3N sodium hydroxide solution the mixture is stirred foran additional 1 hour and subsequently poured into ice-water. Theseparated grey crystals are filtered under suction and taken up in ethylacetate, whereupon the organic phase is dried over magnesium sulfate andthe solvent is distilled. After recrystallization from ethylacetate/hexane there is obtained 3,4-dimethoxy-5-nitrophenyl(1-methylimidazol-2-yl) ketone in the form of colorless crystals of m.p.144°-145°.

b) 5.0 g of 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketoneare treated with 50 ml of hydrobromic acid (48%), whereupon the mixtureis stirred under reflux temperature for 2 hours. After cooling theseparated precipitate is filtered under suction, washed with ice-waterand recrystallized from ethanol. There is obtained3,4-dihydroxy-5-nitrophenyl (1-methyl- imidazol-2-yl) ketonehydrobromide in the form of yellow crystals of decomposition point>240°.

EXAMPLE 68

In analogy to Example 67, from 3,4-dimethoxy-5-nitrobenzoyl chloride and1-benzylimidazole there is obtained 1-benzylimidazol-2-yl(3,4-dimethoxy-5-nitrophenyl) ketone in the form of colorless crystalsof m.p. 134-135° (from methylene chloride/hexane) and therefrom withhydrogen bromide there is obtained 1-benzylimidazol-2-yl(3,4-dihydroxy-5-nitrohenyl) ketone hydrobromide as yellow crystals ofm.p. 218°-219° (dec.).

EXAMPLE 69

a) A solution of 10.0 g of 1-[(benzyloxy)- methyl]imidazole in 50 ml ofacetonitrile is added dropwise within 10 minutes while cooling with iceto a solution of 13.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4g of triethylamine in 80 ml of acetonitrile so that the temperature doesnot exceed 25° . The mixture is subsequently stirred for an additional 3hours, whereupon the solvent is distilled. After treatment with water,the mixture is extracted with ethyl acetate. After two-fold washing withwater, the organic phase is dried over sodium sulfate and evaporated.The resulting oil is chromatographed on 600 g of silica gel withtoluene/ethyl acetate (95:5). There is obtained1-[(benzyloxy)methyl]imidazol-2-yl (3,4-dimethoxy-5-nitrophenyl) ketoneas a yellowish oil.

b) In analogy to Example 67b) there is obtained after treatment withhydrobromic acid 3,4-dihydroxy-5-nitrophenyl (imidazol-2-yl) ketonehydrobromide as yellow crystals of m.p. 247°-248°.

EXAMPLE 70

a) A solution of 25.0 g of 3-bromoquinoline is dissolved in 200 ml ofdry ether and cooled to -60° . At this temperature there are addeddropwise within 15 minutes 75.1 ml of a 1.6 molar solution ofn-butyllithium, whereupon the mixture is stirred for 10 minutes. Asolution of 26.5 g of vanillin benzyl ether in 250 ml of dry ether isadded dropwise thereto at -60°, the mixture is subsequently stirred atroom temperature for 3 hours, poured into about 1.5 1 of ice-water andextracted three times with 600 ml of ethyl acetate each time. Theorganic phase is washed with water, dried over sodium sulfate andevaporated. The resulting oil is chromatographed on 1 kg of silica gelwith methylene chloride/ethyl acetate (1:1). The crystalline crudeproduct obtained is recrystallized from ethyl acetate. There is obtainedα[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in the form ofcolourless crystals of m.p. 124°-125°.

b) A solution of 6.2 g ofα-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in 200 ml ofmethylene chloride is treated with 62 g of manganese dioxide and stirredat the reflux temperature 2 hours. After cooling the precipitate isfiltered under suction and washed with methylene chloride. The filtrateis evaporated and the oil obtained is dissolved in hot ether, whereuponthe solution is treated with a small amount of pentane. The separatedcrystals are filtered under suction. There is obtained4-(benzyloxy)-3-methoxyphenyl (3-quinolinyl) ketone in the form ofcolorless crystals of m.p. 110°-111°.

c) 11.0 g of 4-(benzyloxy)-3-methoxyphenyl (3-quinolinyl) ketone aretreated with 50 ml of trifluoroacetic acid, whereupon the mixture isstirred at room temperature for 2 hours. After distillation of thetrifluoroacetic acid, the residue is treated twice with 50 ml of ethanoleach time and the solvent is distilled each time. The oil obtainedcrystallizes upon treatment with ethanol. After recrystallization fromethanol, there is obtained 4-hydroxy-3-methoxyphenyl (3-quinolinyl)ketone in the form of yellowish crystals of m.p. 196°-197°.

d) A solution of 1.91 ml of 65 percent nitric acid in 20 ml of glacialacetic acid is added dropwise to a solution of 5.5 g of4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone in 300 ml of glacialacetic acid at 150° and the mixture is then stirred at this temperaturefor an additional 2 hours. The mixture is then poured into ice-water andextracted three times with 300 ml of ethyl acetate each time. Theorganic phase is washed five times with 100 ml of water each time, driedover sodium sulfate and evaporated. After treatment of the residue withethyl acetate, there is obtained 4-hydroxy-3-methoxy-5-nitrophenyl(3-quinolinyl) ketone in the form of yellow crystals of m.p. 220°-221°(dec.).

e) 820 mg of 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone aretreated with 50 ml of 48 percent hydrobromic acid and held at the refluxtemperature for 3 hours. After distillation of the hydrobromic acid at50°, the residue is treated with 70 ml of hot water and the insolubleconstituent is filtered under suction. There is obtained3,4-dihydroxy-5-nitrophenyl (3-quinolinyl) ketone hydrobromide in theform of yellow crystals of m.p. 270° (dec.).

EXAMPLE 71

In analogy to Example 70 there is obtainedα-[4-(benzyloxy)-3-methoxyphenyl]-4-quinolinemethanol as colorlesscrystals of m.p. 117°-118° (ethyl acetate), therefrom with manganesedioxide there is obtained 4-(benzyloxy)-3-methoxyphenyl(4-isoquinolinyl) ketone as colorless crystals of m.p. 126.5°-127.5°,therefrom with trifluoroacetic acid there is obtained4-hydroxy-3-methoxyphenyl (4-isoquinolinyl) ketone as yellow crystals ofm.p. 197.5°-198.5° and therefrom by nitration with nitric acid inglacial acetic acid and subsequent treatment with hydrobromic acid,there is obtained 3,4-dihydroxy-5-nitrophenyl (4-isoquinolinyl) ketonehydrobromide as yellow crystals of m.p. 256° (dec.).

EXAMPLE 72

In analogy to Example 70 there is obtainedα-[4-(benzyloxy)-3-methoxyphenyl]-2-naphthalenemethanol as colorlesscrystals (ethyl acetate/hexane) of m.p. 113°-114°, therefrom withmanganese dioxide there is obtained 4-(benzyloxy)-3-methoxyphenyl(2-naphthyl) ketone as colorless crystals (ethyl acetate/hexane) of m.p.104°-105°, therefrom by treatment with trifluoroacetic acid andnitration with nitric acid in glacial acetic acid there is obtained4-hydroxy-3-methoxy-5-nitrophenyl (2-naphthyl) ketone as yellow crystalsof m.p. 187°-188° and therefrom by treatment with hydrobromic acid thereis obtained 3,4-dihydroxy-5-nitrophenyl (2-naphthyl) ketone as yellowcrystals of m.p. 184°-185°.

EXAMPLE 73

a) A solution of 20.0 g of 3-phenylpropyl bromide in 300 ml of ether istreated at -60° while stirring within 15 minutes with a solution of 71.8ml of tert.butyllithium (1.4 molar) in pentane. After 10 minutes thereis added dropwise at this temperature within 15 minutes a solution of22.14 g of vanillin benzyl ether in 200 ml of ether, whereupon themixture is stirred for an additional 2 hours. The mixture is poured into11 of ice-water and extracted three times with 500 ml of ethyl acetateeach time. The organic phase is washed twice with 200 ml of water eachtime, dried over sodium sulfate and evaporated. The oil obtained ischromatographed on 1 kg of silica gel with methylene chloride. Thecrystals obtained are recrystallized from ether/pentane. There isobtained 4-(benzyloxy)-3-methoxy-α-(3-phenylpropyl)benzyl alcohol in theform of colorless crystals of m.p. 71°-73°.

b) A solution of 9.0 g of4-(benzyloxy)-3-methoxy-α-(3-phenylpropyl)benzyl alcohol in 250 ml ofmethylene chloride is treated with 90 g of manganese dioxide and held atthe reflux temperature for 2 hours. After cooling, the precipitate isfiltered under suction and washed with methylene chloride. The filtrateis evaporated and the residue is recrystallized from ethylacetate/ether. There is obtained4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone in the form of colorlesscrystals of m.p. 81°-82°.

c) A solution of 7.0 g of4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone in 40 ml of 33 percenthydrobromic acid in glacial acetic acid is stirred at room temperaturefor 5 hours and subsequently poured into 500 ml of ice-water. Thesolution is adjusted to pH 6.0 by the addition of conc. ammonia andextracted three times with 250 ml of ethyl acetate each time. Theorganic phase is washed three times with 50 ml of water each time, driedover sodium sulfate and evaporated. The oil obtained is dissolved in 20ml of ether, whereupon the solution is treated with hexane until itbecomes turbid and is left to crystallize out. There is obtainedcolorless 4'-hydroxy-3'-methoxy-4-phenylbutyrophenone of m.p. 91°-92°.

d) A solution of 0.79 ml of 65 percent nitric acid in 25 ml of glacialacetic acid is added dropwise to a solution of 2.2 g of4'-hydroxy-3'-methoxy-4- phenylbutyrophenone in 25 ml of glacial aceticacid and the mixture is stirred at room temperature for an additional 2hours. The mixture is poured into 150 ml of ice-water and, aftertreatment with 20 ml of 3N hydrochloric acid, extracted three times with75 ml of ethyl acetate each time. The organic phase is washed withwater, dried over sodium sulfate and evaporated. The crude productobtained is taken up in ethyl acetate and filtered over 75 g of silicagel. After recrystallization from acetonitrile, there is obtained4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone in the form ofyellow crystals of m.p. 120°-121°.

e) 1.0 g of 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone is heldat 200° for 1 hour with 8 g of pyridine hydrochloride. The reactionmixture is poured while still warm into ice-water and extracted withethyl acetate. The organic phase is washed with 1N hydrochloric acid andsubsequently with water, dried over sodium sulfate and evaporated. Thedark residue obtained is chromatographed on a 30-fold amount of silicagel with ethyl acetate. From methylene chloride/hexane there is obtained3',4'-dihydroxy-5'-nitro-4-phenylbutyrophenone in the form of yellowcrystals of m.p. 118°-119°.

EXAMPLE 74

a) A solution of 14.68 g of potassium cyanide in 20 ml of water is addedto a solution of 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde in 100 mlof dioxane. 18.81 ml of 37 percent hydrochloric acid are now addeddropwise thereto within 30 minutes while stirring vigorously. After theaddition of 120 ml of ether, the excess hydrogen cyanide gas is drivenoff by passing argon through the mixture. The reaction mixture isfiltered a siliceous earth filter aid, and the organic phase is washedwith water dried over sodium sulfate and evaporated. Theα-hydroxy-3,4-dimethoxy- phenylacetonitrile (yellowish oil) which isformed is dissolved in 200 ml of ether, whereupon the solution istreated with 20 ml of ethanol, cooled to 0° and hydrochloric acid gas ispassed in for 30 minutes. After 3 hours, the separated colorlessprecipitate is filtered under suction and recrystallized fromethanol/ether. There is obtained ethyl(3,4-dimethoxy-5-nitrophenyl)hydroxy- acetimidate hydrochloride.

b) 19.7 g of ethyl (3,4-dimethoxy-5-nitro-phenyl)hydroxyacetimidate aredissolved in 500 ml of ethanol, 6.73 g of o-phenylenediamine are added,the mixture is stirred at room temperature for 2 hours and subsequentlyheld at the reflux temperature overnight. After distillation of thesolvent, the residue is treated with 50 ml of water, made alkaline withsodium carbonate solution and extracted twice with 250 ml of methylenechloride each time. The organic phase is washed with water, dried oversodium sulfate and evaporated. The orange residue obtained ischromatographed on 400 g of silica gel with methylene chloride/ethylacetate (1:1). From ether/hexane there is obtainedα-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol in the form ofyellowish crystals of m.p. 50° (dec.).

c) 13.2 g of α-(3,4-dimethoxy-5-nitro-phenyl)-2-benzimidazolemethanolare dissolved in 200 ml of methylene chloride and, after treatment with130 g of manganese dioxide, the mixture is stirred at the refluxtemperature for 2 hours. After filtration, the solvent is distilled.There is obtained 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl) ketonein the form of yellowish crystals of m.p. 212°-213°.

d) 1.0 g of 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl) ketone and8.0 g of pyridine hydrochloride are held at 200° for 60 minutes. Thedark solution is poured while still warm into ice-water and extractedthree times with 100 ml of ethyl acetate each time. The organic phase iswashed with water, dried over sodium sulfate and evaporated. Afterrecrystallization from ethyl acetate/hexane, there is obtained2-benzimidazolyl (3,4-dihydroxy-5-nitrophenyl) ketone in the form ofyellow crystals of m.p. 249°-250°

EXAMPLE 75

a) 30.0 g of 3,4-dimethoxy-5-nitrobenzoic acid are dissolved in 250 mlof tetrahydrofuran and, after the addition of 21.85 g of1,1'-carbonyldiimidazole, the mixture is stirred at the refluxtemperature for 2 hours. The mixture is poured into 300 ml of ice-waterand the precipitated crystals are filtered under suction after stirringfor 30 minutes. The crystals are taken up in methylene chloride,whereupon the organic phase is washed with water, dried over sodiumsulfate and evaporated. After crystallization from methylenechloride/hexane, there is obtained 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in the form of colorless crystals of m.p.136°-137°.

b) 10.0 g of 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in 50 ml ofdimethylformamide are treated with 6.95 g of acetamidoxime, whereuponthe mixture is stirred at 70° for 1 hour. After cooling, the mixture ispoured into 500 ml of ice-water and stirred for 30 minutes. Theseparated crystals are filtered under suction and washed with water.After crystallization from ethyl acetate there is obtainedN'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine in the form ofcolorless crystals of m.p. 165°-166°.

c) 2.0 g of N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine are heldat reflux temperature for 1 hour in 20 ml of glacial acetic acid. Afterdistillation of the acetic acid, the crystalline residue isrecrystallized from ether/hexane. There is obtained5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole in the form ofcolorless crystals of m.p. 111°.

d) 2.5 g of 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazoleare dissolved in 70 ml of methylene chloride. After cooling to -60°there is added dropwise thereto within 20 minutes while stirring asolution of 23.62 g of boron tribromide in 50 ml of methylene chloride,whereupon the mixture is held at the reflux temperature for 48 hours.After cooling to -60°, the mixture is treated with 60 ml of ethanol andsubsequently stirred at room temperature for 30 minutes. The yellowsolution is evaporated to dryness, whereupon the residue is treatedthree times with 100 ml of toluene/ethanol (1:1) each time and thesolvent is distilled each time. After crystallization from ethanol,there is obtained 5-(3-methyl-1,2,4-oxadiazol-5- yl)-3-nitropyrocatecholin the form of yellow crystals of m.p. 201°-202°.

EXAMPLE 76

a) 143.8 ml of n-butyllithium solution (1.53M in hexane) are addeddropwise at -70° within 30 minutes to 35.0 g of 1-bromo-2-fluorobenzene(dissolved in 600 ml of tetrahydrofuran). After stirring at -70° for 60minutes 48.5 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 450 mlof tetrahydrofuran) are added dropwise thereto during 30 minutes. Thereaction mixture is stirred at -70° for 2 hours and at 0° for 30minutes, poured into a mixture of ice and 150 ml of 2N sulfuric acid andextracted three times with 500 ml of ether. The combined ether phasesare washed with saturated sodium chloride solution, dried over sodiumsulfate and evaporated. There is obtained4-(benzyloxy)-2'-fluoro-3'-methoxybenzhydrol as a yellowish oil whichcan be used directly in the subsequent reaction step.

In an analogous manner:

a1) From 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-fluorobenzenethere is obtained 4-(benzyloxy)-3'-fluoro-3-methoxybenzhydrol as an oil:

a2) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-4-fluorobenzenethere is obtained 4-(benzyloxy)-4'-fluoro-3-methoxybenzhydrol as an oil;

a3) from 3-methoxy-4-benzyloxybenzaldehyde and1-bromo-2,6-difluorobenzene there is obtained4-(benzyloxy)-2',6'-difluoro-3-methoxybenzhydrol as an oil;

a4) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2-chlorobenzenethere is obtained 4-(benzyloxy)-2'-chloro-3-methoxybenzhydrol as an oil;

a5) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-chlorobenzenethere is obtained 4-(benzyloxy)-3'-chloro-3-methoxybenzhydrol as an oil:

a6) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-4-chlorobenzenethere is obtained 4-(benzyloxy)-4'-chloro-3-methoxybenzhydrol as an oil:

a7) from 4-benzyloxy-3-methoxybenzaldehyde and 2-bromotoluene there isobtained 4-(benzyloxy)-3-methoxy-2'-methylbenzhydrol as an oil;

a8) from 3-methoxy-4-benzyloxybenzaldehyde and 4-bromotoluene there isobtained 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol as an oil:

a9) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromobenzonitrile thereis obtained 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol as an oil and

a10) from 3-methoxy-4-benzyloxybenzaldehyde and1-bromo-2-trifluoromethylbenzene there is obtained4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzhydrol as an oil.

b) 69.8 g of 4-(benzyloxy)-2'-fluoro-3-methoxybenzhydrol (dissolved in600 ml of methylene chloride) are treated within 30 minutes at 20° with45.3 g of pyridinium chlorochromate and stirred at 20° for 3 hours. Theprecipitate formed is subsequently filtered and washed with methylenechloride. The filtrate is evaporated and the residue is filtered on 100g of silica gel with ether. After recrystallization from ether, there isobtained 4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone of m.p.118°-120°.

In an analogous manner:

b1) From 4-(benzyloxy)-3'-fluoro-3-methoxybenzhydrol there is obtained4-(benzyloxy)-3'-fluoro-3-methoxybenzophenone as an amorphous solid:

b2) from 4-(benzyloxy)-4'-fluoro-3-methoxybenzhydrol there is obtained4-(benzyloxy)-4'-fluoro-3-methoxybenzophenone of m.p. 99°-101° (fromether/hexane):

b3) from 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzhydrol there isobtained 4-(benzyloxy)-2,6'-difluoro-3-methoxybenzophenone of m.p.139°-141° (from methylene chloride/ether):

b4) from 4-(benzyloxy)-2'-chloro-3-methoxybenzhydrol there is obtained4-(benzyloxy)-2'-chloro-3-methoxybenzophenone of m.p. 128°-130° (fromether):

b5) from 4-(benzyloxy)-3'-chloro-3-methoxybenzhydrol there is obtained4-(benzyloxy)-3'-chloro-3-methoxybenzophenone as an amorphous solid:

b6) from 4-(benzyloxy)-4'-chloro-3-methoxybenzhydrol there is obtained4-(benzyloxy)-4'-chloro-3-methoxybenzophenone of m.p. 106°-108° (frommethylene chloride/hexane):

b7) from 4-(benzyloxy)-3-methoxy-2'-methylbenzhydrol there is obtained4-(benzyloxy)-3-methoxy-2'-methylbenzophenone of m.p. 86°-88° (fromisopropyl ether):

b8) from 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol there is obtained4-(benzyloxy)-3-methoxy-4'-methylbenzophenone of m.p. 79°-81° (fromether/hexane):

b9) from 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol there is obtained4-(benzyloxy)-2'-cyano-3-methoxybenzophenone as an amorphous solid and

b10) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzhydrol thereis obtained 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzophenone ofm.p. 103°-105° (from ether).

c) 170 ml of 33 percent hydrobromic acid in glacial acetic acid areadded at 20°-25° within 20 minutes to 42.4 g of4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone (dissolved in 450 ml ofmethylene chloride). After stirring at 20° for 1.5 hours, the reactionmixture is poured into 750 ml of ice-water; the methylene chloride phaseis separated and the aqueous phase is extracted twice more with 200 mlof methylene chloride. The combined methylene chloride phases are washedwith 1200 ml of water, dried over sodium sulfate and evaporated. Inorder to remove the resulting benzyl bromide, the oily residue istreated with hexane and decanted off. There is obtained2'-fluoro-4-hydroxy-3-methoxybenzophenone as a yellowish oil which canbe used directly in the subsequent reaction step.

In an analogous manner:

c1) From 4-(benzyloxy)-3'-fluoro-3-methoxybenzophenone there is obtained3'-fluoro-4-hydroxy-3-methoxybenzo- phenone of m.p. 133°-135° (frommethylene chloride/low- boiling petroleum ether);

c2) from 4-(benzyloxy)-4'-fluoro-3-methoxybenzophenone there is obtained4'-fluoro-4-hydroxy-3-methoxybenzo- phenone of m.p. 139°-141° (fromether);

c3) from 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzophenone there isobtained 2',6'-difluoro-b 4-hydroxy-3-methoxybenzophenone of m.p.130°-132° (from methylene chloride/low-boiling petroleum ether);

c4) from 4-(benzyloxy)-2'-chloro-3-methoxybenzophenone there is obtained2'-chloro-4-hydroxy-3-methoxybenzo- phenone as an amorphous solid;

c5) from 4-(benzyloxy)-3'-chloro-3-methoxybenzophenone there is obtained3'-chloro-4-hydroxy-3-methoxybenzo- phenone of m.p. 136°-138° (frommethylene chloride);

c6) from 4-(benzyloxy)-4'-chloro-3-methoxybenzophenone there is obtained4'-chloro-4-hydroxy-3-methoxybenzo- phenone of m.p. 114°-116° (frommethylene chloride/low- boiling petroleum ether);

c7) from 4-(benzyloxy)-3-methoxy-2'-methylbenzophenone there is obtained4-hydroxy-3-methoxy-2'-methylbenzo- phenone of m.p. 103°-105° (fromisopropyl ether);

c8) from 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone there is obtained4-hydroxy-3-methoxy-4'-methylbenzo- phenone of m.p. 103°-105° (fromether/low-boiling petroleum ether);

c9) from 4-(benzyloxy)-2'-cyano-3-methoxybenzophenone there is obtained2'-cyano-4-hydroxy-3-methoxybenzophenone of m.p. 124°-126° (fromether/n-hexane) and

c10) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzophenone thereis obtained 4-hydroxy-3-methoxy-2'-(trifluoromethyl)benzophenone of m.p.115°-117° (from ether).

d) 7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20minutes to 29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone(dissolved in 450 ml of acetic acid). After stirring for 1.5 hours, thereaction mixture is poured into 2 1 of ice-water and the precipitateformed is filtered off, washed with water and dissolved in methylenechloride. The methylene chloride solution is washed with water, driedover sodium sulfate and evaporated. The residue is recrystallized frommethanol. There is obtained2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p. 127°-129°.

In an analogous manner:

d1) From 3,-fluoro-4-hydroxy-3-methoxybenzophenone there is obtained3,-fluoro-4-hydroxy-3-methoxy-5-nitrobenzo- phenone of m.p. 168°-170°(from methanol):

d2) from 4,-fluoro-4-hydroxy-3-methoxybenzophenone there is obtained4,-fluoro-4-hydroxy-3-methoxy-5-nitrobenzo- phenone of m.p. 126°-128°(from ether):

d3) from 2',6'-difluoro-4-hydroxy-3-methoxybenzophenone there isobtained 2,,6,-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p.147°-149° (from methanol):

d4) from 2,-chloro-4-hydroxy-3-methoxybenzophenone there is obtained2,-chloro-4-hydroxy-3-methoxy-5-nitrobenzo- phenone of m.p. 123°-125°(from ether):

d5) from 3'-chloro-4-hydroxy-3-methoxybenzophenone there is obtained3'-chloro-4-hydroxy-3-methoxy-5-nitrobenzo- phenone of m.p. 152°-154°(from methanol):

d6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone there is obtained4'-chloro-4-hydroxy-3-methoxy-5-nitrobenzo- phenone of m.p. 129°-131°(from methylene chloride/low- boiling petroleum ether):

d7) from 4-hydroxy-3-methoxy-2'-methylbenzophenone there is obtained4-hydroxy-3-methoxy-2-methyl-5-nitrobenzo- phenone of m.p. 125°-127°(from ethanol):

d8) from 4-hydroxy-3-methoxy-4'-methylbenzophenone there is obtained4-hydroxy-3-methoxy-4-methyl-5-nitrobenzo- phenone of m.p. 137°-139°(from methylene chloride/ether):

d9) from 2'-cyano-4-hydroxy-3-methoxybenzophenone there is obtained2'-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p. 163°-164° (frommethanol):

d10) from 4-hydroxy-3-methoxy-2'-(trifluoromethyl)-benzophenone there isobtained 4-hydroxy-3-methoxy-5-nitro-2'-(trifluoromethyl)benzophenone ofm.p. 138°-140° (from methylene chloride/low-boiling petroleum ether):

d11) from 4-hydroxy-3,4'-dimethoxybenzophenone there is obtained4-hydroxy-3',4'-dimethoxy-5-nitrobenzophenone of m.p. 134°-136° (frommethanol) and

d12) from 4-hydroxy-3,3',4'-trimethoxybenzophenone there is obtained4-hydroxy-5-nitro-3,3',4'-trimethoxybenzophenone of m.p. 178°-180° (frommethanol).

e) 24.8 g of 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone(dissolved in 120 ml of glacial acetic acid, 100 ml of 33 percenthydrobromic acid in glacial acetic acid and 68 ml of 48 percent aqueoushydrobromic acid) are boiled under reflux for 4 hours. The reactionmixture is subsequently evaporated under reduced pressure and theresidue is distilled with toluene. The residue is dissolved in methylenechloride, washed with water, dried over sodium sulfate, filtered andevaporated. The product is crystallized from methylenechloride/low-boiling petroleum ether. There is obtained2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone of m.p. 169°-171°.

In an analogous manner:

e1) From 3'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 3'-fluoro-3,4-dihydroxy-5-nitrobenzophenone of m.p. 124°-126°(from methylene chloride):

e2) from 4'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 4'-fluoro-3,4-dihydroxy-5-nitrobenzophenone of m.p. 171°-173°(from methylene chloride):

e3) from 2',6'-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 2',6'-difluoro-3,4-dihydroxy-5-nitrobenzophenone of m.p.194°-196° (from methanol):

e4) from 2'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 2,-chloro-3,4-dihydroxy-5-nitrobenzophenone of m.p. 129°-131°(from methylene chloride/low-boiling petroleum ether):

e5) from 3,-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 3,-chloro-3,4-dihydroxy-5-nitrobenzophenone of m.p. 143°-145°(from methylene chloride/low-boiling petroleum ether);

e6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone there is obtained4'-chloro-3,4-dihydroxybenzophenone of m.p. 174°-176° (from methylenechloride):

e7) from 4-hydroxy-3-methoxy-2'-methyl-5-nitrobenzophenone there isobtained 3,4-dihydroxy-2'-methyl-5-nitrobenzophenone of m.p. 164°-166°(from methylene chloride

e8) from 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone there isobtained 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone of m.p. 146°-148°(from methylene chloride):

e9) from 2'-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenone there isobtained 2'-cyano-3,4-dihydroxy-5-nitrobenzophenone of m.p. 159°-161°(from methanol):

e10) from 4-hydroxy-3-methoxy-5-nitro-2'-(trifluoromethyl)benzophenonethere is obtained 3,4-dihydroxy-5-nitro-2'-(trifluoromethyl)benzophenoneof m.p. 146°-148° (from methanol):

e11) from 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenone there is obtained5-nitro-3,4,4'-trihydroxybenzophenone of m.p. 212°-214° (frommethanol/methylene chloride) and

e12) from 4-hydroxy-5-nitro-3,3',4'-trimethoxybenzo- phenone there isobtained 5-nitro-3,3',4,4'-tetrahydroxybenzophenone of m.p. 222°-224°(from ether).

EXAMPLE 77

A suspension of 13.8 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenoneis treated with 9.0 g of 1-(phenethyl)-2-thiourea in 150 ml of n-butanoland the mixture is heated to boiling under reflux for 3 hours. Aftercooling to room temperature, the crystals are filtered under suction andcrystallized from n-butanol. There is obtained3-nitro-5-[2-(phenethylamino)-4-thiazolyl]pyrocatechol hydrobromide ofm.p. 249°-251°.

EXAMPLE 78

In analogy to Example 38, from 2-bromo-3',440-dihydroxy-5'-nitroacetophenone and 2-aminobenzophenone there isobtained 2-(3,4-dihydroxy-5-nitrobenzoyl)-3- phenylindole of m.p.196°-198° (from isopropanol).

EXAMPLE 79

A suspension of 8.3 g of 2-bromo-3',440 -dihydroxy-5'-nitroacetophenoneis treated with 1-(1-adamantyl)-2-thiourea in 90 ml of n-butanol and themixture is heated to boiling under reflux for 4 hours. After cooling toroom temperature, the crystals are filtered under suction andrecrystallized from n-butanol. There is obtained5-[2-(1-adamantylamino)-5-thiazolyl]-3-nitropyrocatechol hydrobromide ofm.p. 245°-247°.

EXAMPLE 80

A suspension of 2.6 g of (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate in20 ml of ethanol and 20 ml of 1N hydrochloric acid is heated to boilingunder reflux for 5 hours. The reaction mixture is then evaporated, theresidue is distilled with toluene and then recrystallized from ethanol.There is obtained 2,3',4'-trihydroxy-5'-nitroacetophenone of m.p.208°-210°.

EXAMPLE 81

A solution of 4.0 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and1.5 g of diaminomaleonitrile in 35 ml of ethanol is heated to boilingunder reflux for 24 hours. The alcohol is then distilled , the residueis dissolved in ether, washed with water, dried over sodium sulfate,filtered and evaporated. There is obtained6-hydroxy-5-(3,4-dihydroxy-5-nitrophenyl)-2,3-pyrazinedicarbonitrile ofm.p. >300° (from ether/methylene chloride).

EXAMPLE 82

a) 4.2 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile dissolved in 150ml of methylene chloride are treated with 8.9 ml of boron tribromide.The reaction mixture is stirred at 20° for 18 hours. It is subsequentlypoured into 220 ml of saturated sodium hydrogen carbonate solution and100 g of ice, adjusted to pH 6 with glacial acetic acid and extractedwith ethyl acetate. The organic phase is washed with water, dried oversodium sulfate and evaporated. There is obtained 5-(bromoacetyl)-2,3-dihydroxybenzonitrile as an amorphous solid.

b) 3.8 g of 5-(bromoacetyl)-2,3-dihydroxybenzonitrile dissolved in 25 mlof N,N-dimethylformamide are treated with N-phenylthiourea and stirredat 100° for 5 hours. Thereafter, the solvent is removed by evaporation.The residue is treated with 200 ml of 1N sodium carbonate solution andextracted three times with 100 ml of methylene chloride each time. Thecombined organic phases are washed with water, dried over sodium sulfateand evaporated. The residue is chromatographed on 30 g of silica gelwith ethyl acetate. The thus-obtained crude product is treated with 40ml of 1N hydrochloric acid, evaporated and crystallized from acetone.There is obtained 5-(2-anilino-4-thiazolyl)-2,3-dihydroxybenzo- nitrilehydrochloride of m.p. 245°-247°.

EXAMPLE 83

a) 25 ml of tert.-butyllithium solution (1.4M in hexane) are addeddropwise at -70° within 10 minutes to 10 g of4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 100 ml oftetrahydrofuran. After stirring at -70° for 1 hour, 5 g ofquinoline-4-carbaldehyde dissolved in 50 ml of tetrahydrofuran are addeddropwise within 30 minutes. The reaction mixture is stirred at -40° for1 hour and at -5° for 1 hour, poured into 200 ml of water and adjustedto pH 4 with glacial acetic acid. The mixture is extracted three timeswith 50 ml of ether each time. The combined ether phases are washed withwater, dried over sodium sulfate and evaporated. There is obtainedα-[4-(benzyloxy)-3-methoxyphenyl]-4-quinolinemethanol as an amorphoussolid.

b) 9.4 g of α-[4-(benzyloxy)-3-methoxyphenyl]-4-quinolinemethanoldissolved in 200 ml of methylene chloride are treated with 6.5 g ofpyridinium chlorochromate, whereupon the mixture is stirred at roomtemperature for 3 hours. The insoluble constituents are subsequentlyfiltered off. The filtrate is evaporated and the residue ischromatographed on 150 g of silica gel with ethyl acetate. There is thusobtained 4-(benzyloxy)-3- methoxyphenyl 4-quinolyl ketone as anamorphous solid.

c) 15 ml of 33 percent hydrobromic acid in glacial acetic acid are addeddropwise within 5 minutes at room temperature to 7.5 g of4-(benzyloxy)-3-methoxyphenyl 4-quinolyl ketone dissolved in 150 ml ofmethylene chloride. After stirring at 20° for 4.5 hours, the reactionmixture is poured portionwise into 250 ml of saturated sodiumbicarbonate solution. The methylene chloride phase is separated; theaqueous phase is extracted twice with 100 ml of methylene chloride eachtime. The combined methylene chloride phases are dried over sodiumsulfate and evaporated. The residue is recrystallized from methylenechloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 4-quinolylketone of m.p. 190°-192°.

d) 0.37 ml of 65 percent nitric acid is added dropwise at roomtemperature to 1.3 g of 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone.After stirring for 3 hours the reaction mixture is poured intoice-water, adjusted to pH 6 with conc. ammonia and the precipitateformed is filtered. The thus-obtained residue is heated under reflux in20 ml of acetonitrile, whereupon the crystals are filtered at 0°. Thereis obtained 4-hydroxy-3-methoxy-5-nitrophenyl 4-quinolyl ketone of m.p.246°-248°.

e) 1 g of 4-hydroxy-3-methoxy-5-nitrophenyl 4-quinolyl ketone dissolvedin 30 ml of 48 percent aqueous hydrobromic acid is stirred at 100° for18 hours. After cooling to room temperature, the reaction mixture isdiluted with 30 ml of water and the precipitate is filtered undersuction. There is obtained 3,4-dihydroxy-5-nitrophenyl 4-quinolyl ketonehydrobromide of m.p. 273°-275° (from acetonitrile).

EXAMPLE 84

a) 18.8 ml of n-butyllithium solution (1.6M in hexane) are addeddropwise at -50° within 10 minutes to 4.03 g of thiophene dissolved in40 ml of tetrahydrofuran. After stirring at -50° for 30 minutes 6.3 g of3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 100 ml of tetrahydrofuranare added dropwise within 30 minutes. The reaction mixture is stirred at-50° for 1 hour at 0° for 30 minutes and poured into 100 ml of 2Nsulphuric acid. The mixture is extracted three times with 100 ml ofether each time: the combined ether phases are washed with sodiumchloride solution, dried over sodium sulfate, filtered and evaporated.There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanol ofm.p. 79°-81° (from methylene chloride/hexane).

b) 9.9 g of α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanoldissolved in 300 ml of acetone are treated with 90 g of manganesedioxide and heated under reflux for 4 hours. The manganese dioxide isremoved by suction filtration and the filtrate is evaporated. There isobtained 3,4-dimethoxy-5-nitrophenyl 2-thienyl ketone of m.p. 102°-104°(from methylene chloride/hexane).

c) 2 g of 3,4-dimethoxy-5-nitrophenyl 2-thienyl ketone are stirred at100° for 8 hours in a mixture of 20 ml of 30-33 percent hydrobromic acidin glacial acetic acid and 20 ml of 48 percent aqueous hydrobromic acid.The reaction mixture is subsequently evaporated to dryness. The residueis taken up in ethyl acetate, washed with water, dried over sodiumsulfate and filtered, and the filtrate is evaporated. Afterrecrystallization from ethyl acetate/hexane there is obtained3,4-dihydroxy-5-nitrophenyl 2-thienyl ketone of m.p. 155°-157°.

EXAMPLE A

The interlocking gelatine capsules of the following composition can beprepared in a known manner:

    ______________________________________                                                              Amount in mg/                                           Ingredients           capsules                                                ______________________________________                                        L-Dopa                100                                                     Benserazide hydrochloride                                                                            29.3                                                   3,4-Dihydroxy-5-nitrophenyl                                                                          25                                                     4-pyridyl ketone                                                              Gelatine               1                                                      Magnesium stearate     1                                                      Avicel                 93.7                                                   Mannitol              100                                                     Capsule fill weight   350 mg                                                  ______________________________________                                    

We claim:
 1. A compound of the formula: ##STR24## wherein Ra is nitro orcyano, Rb is hydrogen or halogen and Rc' is COR¹¹ wherein R¹¹ is anaromatic or partially unsaturated heterocyclic group attached via a ringcarbon atom and having 1-3 nitrogen atoms as hetero ring members,or anester or ether derivative thereof which is hydrolyzable underphysiological conditions or a pharmaceutically acceptable salt thereof.2. A compound, according to claim 1, wherein Rb is situated in thep-position to Ra.
 3. A compound, according to claim 2, wherein Ra isnitro.
 4. A compound, according to claim 3, wherein Rb is hydrogen,chlorine or fluorine.
 5. A compound, according to claim 4, wherein Rb ishydrogen.
 6. A compound, according to claim 5, wherein Rc' is the group-CO-R¹¹ and R¹¹ is an aromatic, mononuclear heterocyclic group with 1-3nitrogen atoms as the hetero ring member(s) which is attached via acarbon atom.
 7. A compound, according to Claim 6, wherein R¹¹ is apyridyl group.
 8. A compound, according to claim 1,3,4-Dihydroxy-5-nitrophenyl 4-pyridyl ketone.
 9. A compound according toclaim 1, 3,4-dihydroxy-5-nitrophenyl 3-pyridyl ketone.
 10. Apharmaceutical composition comprising a compound of the formula:##STR25## wherein Ra is nitro or cyano, Rb is hydrogen or halogen andRc' is COR¹ wherein R¹ is an aromatic or partially unsaturatedheterocyclic group attached via a ring carbon atom and having 1-3nitrogen atoms as hetero ring members,or an ester or ether derivativethereof which is hydrolyzable under physiological conditions or apharmaceutically acceptable salt thereof, and a therapeutically inertcarrier material.
 11. A pharmaceutical composition, according to claim10, wherein the compound of formula Ia is 3,4-dihydroxy-5-nitrophenyl4-pyridyl ketone.
 12. A pharmaceutical composition according to claim10, wherein the compound of formula Ia is 3,4-dihydroxy-5-nitrophenyl3-pyridyl ketone.
 13. A pharmaceutical composition comprising L-dopa,peripheral decarboxylase inhibitor, a compound of the formula: ##STR26##wherein Ra is nitro or cyano, Rb is hydrogen or halogen and Rc' is COR¹wherein R¹ is an aromatic or partially unsaturated heterocyclic groupattached via a ring carbon atom and having 1-3 nitrogen atoms as heretoring members,or an ester or ether derivative thereof which ishydrolyzable under physiological conditions or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier material.14. A pharmaceutical composition according to claim 10, wherein R¹ ispyridyl.
 15. A pharmaceutical composition according to claim 14, whereinthe compound of formula Ia is 3,4-dihydroxy-5-nitrophenyl 3-pyridylketone.
 16. A pharmaceutical composition for treating depressioncomprising an effective amount of a compound of the formula: ##STR27##wherein Ra is nitro or cyano, Rb is hydrogen or halogen and Rc' is COR¹wherein R^(l) is an aromatic or partially unsaturated heterocyclic groupattached via a ring carbon atom and having 1-3 nitrogen atoms as heretoring members,or an ester or ether derivative thereof which ishydrolyzable under physiological conditions or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier material.17. A pharmaceutical composition according to claim 16, wherein R¹ ispyridyl.
 18. A pharmaceutical composition according to claim 17, whereinthe compound of formula Ia is 3,4-dihydroxy-5-nitrophenyl 3-pyridylketone.
 19. A pharmaceutical composition for treating Parkinson'sdisease comprising L-dopa, a peripheral decarboxylase inhibitor, acompound of the formula: ##STR28## wherein Ra is nitro or cyano, Rb ishydrogen or halogen and Rc' is COR¹ wherein R¹ is an aromatic orpartially unsaturated heterocyclic group attached via a ring carbon atomand having 1-3 nitrogen atoms as hereto ring members,or an ester orether derivative thereof which is hydrolyzable under physiologicalconditions or a pharmaceutically acceptable salt thereof, and atherapeutically inert carrier material.
 20. A pharmaceutical compositionaccording to claim 19, wherein R¹ is pyridyl.
 21. A pharmaceuticalcomposition according to claim 20, wherein the compound of formula Ia is3,4-dihydroxy-5-nitrophenyl 3-pyridyl ketone.
 22. A pharmaceuticalcomposition for inhibiting catechol-O-methyl-transferase, saidcomposition comprising a catechol-O-methyl transferase inhibiting amountof a compound of the formula: ##STR29## wherein Ra is nitro or cyano, Rbis hydrogen or halogen and Rc' is COR¹ wherein R¹ is an aromatic orpartially unsaturated heterocyclic group attached via a ring carbon atomand having 1-3 nitrogen atoms as hereto ring members,or an ester orether derivative thereof which is hydrolyzable under physiologicalconditions or a pharmaceutically acceptable salt thereof, and atherapeutically inert carrier material.
 23. A pharmaceutical compositionaccording to claim 22, wherein R¹ is pyridyl.
 24. A pharmaceuticalcomposition according to claim 23, wherein the compound of formula Ia is3,4-dihydroxy-5-nitrophenyl 3-pyridyl ketone.